ALBERT

Description: We study four citrate synthase homodimeric proteins within a structure-based coarse-grained model. Two of these proteins come from thermophilic bacteria, one from a cryophilic bacterium and one from a mesophilic organism; three are in the closed and two in the open conformations. Even though the proteins belong to the same fold, the model distinguishes the properties of these proteins in a way which is consistent with experiments. For instance, the thermophilic proteins are more stable thermodynamically than their mesophilic and cryophilic homologues, which we observe both in the magnitude of thermal fluctuations near the native state and in the kinetics of thermal unfolding. The level of stability correlates with the average coordination number for amino acid contacts and with the degree of structural compactness. The pattern of positional fluctuations along the sequence in the closed conformation is different than in the open conformation, including within the active site. The modes of correlated and anticorrelated movements of pairs of amino acids forming the active site are very different in the open and closed conformations. Taken together, our results show that the precise location of amino acid contacts in the native structure appears to be a critical element in explaining the similarities and differences in the thermodynamic properties, local flexibility, and collective motions of the different forms of the enzyme.

Description: In this paper, we examine the behaviour of basic autocatalytic feedback modules involving a species catalyzing its own production, either directly or indirectly. We first perform a systematic study of the autocatalytic feedback module in isolation, examining the effect of different factors, showing how this module is capable of exhibiting monostable threshold and bistable switch-like behaviour. We then study the behaviour of this module embedded in different kinds of basic networks including (essentially) irreversible cycles, open and closed reversible chains, and networks with additional feedback. We study the behaviour of the networks deterministically and also stochastically, using simulations, analytical work, and bifurcation analysis. We find that (i) there are significant differences between the behaviour of this module in isolation and in a network: thresholds may be altered or destroyed and bistability may be destroyed or even induced, even when the ambient network is simple. The global characteristics and topology of this network and the position of the module in the ambient network can play important and unexpected roles. (ii) There can be important differences between the deterministic and stochastic dynamics of the module embedded in networks, which may be accentuated by the ambient network. This provides new insights into the functioning of such enzymatic modules individually and as part of networks, with relevance to other enzymatic signalling modules as well.

Description: Recent experiments indicate a connection between the structure of amyloid aggregates and their cytotoxicity as related to neurodegenerative diseases. Of particular interest is the Iowa Mutant, which causes early-onset of Alzheimer's disease. While wild-type Amyloid β -peptides form only parallel beta-sheet aggregates, the mutant also forms meta-stable antiparallel beta sheets. Since these structural variations may cause the difference in the pathological effects of the two A β -peptides, we have studied in silico the relative stability of the wild type and Iowa mutant in both parallel and antiparallel forms. We compare regular molecular dynamics simulations with such where the viscosity of the samples is reduced, which, we show, leads to higher sampling efficiency. By analyzing and comparing these four sets of all-atom molecular dynamics simulations, we probe the role of the various factors that could lead to the structural differences. Our analysis indicates that the parallel forms of both wild type and Iowa mutant aggregates are stable, while the antiparallel aggregates are meta-stable for the Iowa mutant and not stable for the wild type. The differences result from the direct alignment of hydrophobic interactions in the in-register parallel oligomers, making them more stable than the antiparallel aggregates. The slightly higher thermodynamic stability of the Iowa mutant fibril-like oligomers in its parallel organization over that in antiparallel form is supported by previous experimental measurements showing slow inter-conversion of antiparallel aggregates into parallel ones. Knowledge of the mechanism that selects between parallel and antiparallel conformations and determines their relative stability may open new avenues for the development of therapies targeting familial forms of early-onset Alzheimer's disease.

Description: Hemoprotein mimics, cobalt picket fence porphyrins have been prepared in the gas phase as neutral molecules for the first time. Their ligation properties have been studied with 1-methylimidazole and compared with those of other cobalt porphyrins, tetraphenyl porphyrin, and cobalt protoporphyrin IX chloride, in view of studying the sterical properties of the ligation. It is shown that the cobalt picket fence porphyrin can only accept one 1-methylimidazole ligand in contrast to less sterically crowded porphyrins like cobalt tetraphenylporphyrin that present two accessible ligation sites. The femtosecond dynamics of these ligated systems have been studied after excitation at 400 nm, in comparison with the unligated ones. The observed transients are formed in much shorter times, 30 fs for the ligated species, as compared to free species (100 fs), supporting the porphyrin to metal charge transfer nature of these transients. The similar decays of the ligated transients

Description: DNA-binding proteins locate and bind their target sequences positioned on DNA in crowded environments, but the molecular crowding effect on this search process is not clear. Using analytical techniques and Langevin dynamics simulations in two dimensions (2D), we find that the essential physics for facilitated diffusion in 2D search and 3D search is the same. We observe that the average search times have minima at the same optimal nonspecific binding energy for the cases with and without the crowding particle. Moreover, the molecular crowding increases the search time by increasing the average search rounds and the one-dimensional (1D) sliding time of a round, but almost not changing the average 2D diffusion time of a round. In addition, the fraction of 1D sliding time out of the total search time increases with increasing the concentration of crowders. For 2D diffusion, the molecular crowding decreases the jumping length and narrows its distribution due to the cage effect from crowders. These results shed light on the role of facilitated diffusion in DNA targeting kinetics in living cells.

Description: Protein conformation and orientation in the lipid membrane plays a key role in many cellular processes. Here we use molecular dynamics simulation to investigate the relaxation and C-terminus diffusion of a model helical peptide: beta-amyloid (Aβ) in a lipid membrane. We observed that after the helical peptide was initially half-embedded in the extracelluar leaflet of phosphatidylcholine (PC) or PC/cholesterol (PC/CHOL) membrane, the C-terminus diffused across the membrane and anchored to PC headgroups of the cytofacial lipid leaflet. In some cases, the membrane insertion domain of the Aβ was observed to partially unfold. Applying a sigmoidal fit to the process, we found that the characteristic velocity of the C-terminus, as it moved to its anchor site, scaled with θ u −4/3 , where θ u is the fraction of the original helix that was lost during a helix to coil transition. Comparing this scaling with that of bead-spring models of polymer relaxation suggests that the C-terminus velocity is highly regulated by the peptide helical content, but that it is independent of the amino acid type. The Aβ was stabilized by the attachment of the positive Lys28 side chain to the negative phosphate of PC or 3β oxygen of CHOL in the extracellular lipid leaflet and of the C-terminus to its anchor site in the cytofacial lipid leaflet.

Description: We present a method to obtain numerically accurate values of configurational free energies of semiflexible macromolecular systems, based on the technique of thermodynamic integration combined with normal-mode analysis of a reference system subject to harmonic constraints. Compared with previous free-energy calculations that depend on a reference state, our approach introduces two innovations, namely, the use of internal coordinates to constrain the reference states and the ability to freely select these reference states. As a consequence, it is possible to explore systems that undergo substantially larger fluctuations than those considered in previous calculations, including semiflexible biopolymers having arbitrary ratios of contour length L to persistence length P . To validate the method, high accuracy is demonstrated for free energies of prime DNA knots with L / P = 20 and L / P = 40, corresponding to DNA lengths of 3000 and 6000 base pairs, respectively. We then apply the method to study the free-energy landscape for a model of a synaptic nucleoprotein complex containing a pair of looped domains, revealing a bifurcation in the location of optimal synapse (crossover) sites. This transition is relevant to target-site selection by DNA-binding proteins that occupy multiple DNA sites separated by large linear distances along the genome, a problem that arises naturally in gene regulation, DNA recombination, and the action of type-II topoisomerases.

Description: Since the time of Kirkwood, observed deviations in magnitude of the dielectric constant of aqueous protein solution from that of neat water (∼80) and slower decay of polarization have been subjects of enormous interest, controversy, and debate. Most of the common proteins have large permanent dipole moments (often more than 100 D) that can influence structure and dynamics of even distant water molecules, thereby affecting collective polarization fluctuation of the solution, which in turn can significantly alter solution's dielectric constant. Therefore, distance dependence of polarization fluctuation can provide important insight into the nature of biological water. We explore these aspects by studying aqueous solutions of four different proteins of different characteristics and varying sizes, chicken villin headpiece subdomain (HP-36), immunoglobulin binding domain protein G (GB1), hen-egg white lysozyme (LYS), and Myoglobin (MYO). We simulate fairly large systems consisting of single protein molecule and 20000–30000 water molecules (varied according to the protein size), providing a concentration in the range of ∼2–3 mM. We find that the calculated dielectric constant of the system shows a noticeable increment in all the cases compared to that of neat water. Total dipole moment auto time correlation function of water ⟨δ M W (0)δ M W ( t )⟩ is found to be sensitive to the nature of the protein. Surprisingly, dipole moment of the protein and total dipole moment of the water molecules are found to be only weakly coupled. Shellwise decomposition of water molecules around protein reveals higher density of first layer compared to the succeeding ones. We also calculate heuristic effective dielectric constant of successive layers and find that the layer adjacent to protein has much lower value (∼50). However, progressive layers exhibit successive increment of dielectric constant, finally reaching a value close to that of bulk 4–5 layers away. We also calculate shellwise orientational correlation function and tetrahedral order parameter to understand the local dynamics and structural re-arrangement of water. Theoretical analysis providing simple method for calculation of shellwise local dielectric constant and implication of these findings are elaborately discussed in the present work.

Description: Hydrogenase enzymes are important because they can reversibly catalyze the production of molecular hydrogen. Proton transport mechanisms have been previously studied in residue pathways that lead to the active site of the enzyme via residues Cys299 and Ser319. The importance of this pathway and these residues has been previously exhibited through site-specific mutations, which were shown to interrupt the enzyme activity. It has been shown recently that a separate water channel (WC2) is coupled with electron transport to the active site of the [FeFe]-hydrogenase. The water-mediated proton transport mechanisms of the enzyme in different electronic states have been studied using the multistate empirical valence bond reactive molecular dynamics method, in order to understand any role WC2 may have in facilitating the residue pathway in bringing an additional proton to the enzyme active site. In a single electronic state A 2− , a water wire was formed through which protons can be transported with a low free energy barrier. The remaining electronic states were shown, however, to be highly unfavorable to proton transport in WC2. A double amino acid substitution is predicted to obstruct proton transport in electronic state A 2- by closing a cavity that could otherwise fill with water near the proximal Fe of the active site.

Description: We propose a discrete transition-based reweighting analysis method (dTRAM) for analyzing configuration-space-discretized simulation trajectories produced at different thermodynamic states (temperatures, Hamiltonians, etc.) dTRAM provides maximum-likelihood estimates of stationary quantities (probabilities, free energies, expectation values) at any thermodynamic state. In contrast to the weighted histogram analysis method (WHAM), dTRAM does not require data to be sampled from global equilibrium, and can thus produce superior estimates for enhanced sampling data such as parallel/simulated tempering, replica exchange, umbrella sampling, or metadynamics. In addition, dTRAM provides optimal estimates of Markov state models (MSMs) from the discretized state-space trajectories at all thermodynamic states. Under suitable conditions, these MSMs can be used to calculate kinetic quantities (e.g., rates, timescales). In the limit of a single thermodynamic state, dTRAM estimates a maximum likelihood reversible MSM, while in the limit of uncorrelated sampling data, dTRAM is identical to WHAM. dTRAM is thus a generalization to both estimators.

Description: The hydration layer surrounding a protein plays an essential role in its biochemical function and consists of a heterogeneous ensemble of water molecules with different local environments and different dynamics. What determines the degree of dynamical heterogeneity within the hydration shell and how this changes with temperature remains unclear. Here, we combine molecular dynamics simulations and analytic modeling to study the hydration shell structure and dynamics of a typical globular protein, ubiquitin, and of the spruce budworm hyperactive antifreeze protein over the 230–300 K temperature range. Our results show that the average perturbation induced by both proteins on the reorientation dynamics of water remains moderate and changes weakly with temperature. The dynamical heterogeneity arises mostly from the distribution of protein surface topographies and is little affected by temperature. The ice-binding face of the antifreeze protein induces a short-ranged enhancement of water structure and a greater slowdown of water reorientation dynamics than the non-ice-binding faces whose effect is similar to that of ubiquitin. However, the hydration shell of the ice-binding face remains less tetrahedral than the bulk and is not “ice-like”. We finally show that the hydrogen bonds between water and the ice-binding threonine residues are particularly strong due to a steric confinement effect, thereby contributing to the strong binding of the antifreeze protein on ice crystals.

Description: Numerous experiments have demonstrated that many classes of organic reactions exhibit increased reaction rates when performed in heterogeneous water emulsions. Despite enormous practical importance of the observed “on-water” catalytic effect and several mechanistic studies, its microscopic origins remains unclear. In this work, the second generation Car-Parrinello molecular dynamics method is extended to self-consistent charge density-functional based tight-binding in order to study “on-water” catalysis of the Diels-Alder reaction between dimethyl azodicarboxylate and quadricyclane. We find that the stabilization of the transition state by dangling hydrogen bonds exposed at the aqueous interfaces plays a significantly smaller role in “on-water” catalysis than has been suggested previously.

Description: We develop efficient handling of solvation forces in the multiscale method of multiple time step molecular dynamics (MTS-MD) of a biomolecule steered by the solvation free energy (effective solvation forces) obtained from the 3D-RISM-KH molecular theory of solvation (three-dimensional reference interaction site model complemented with the Kovalenko-Hirata closure approximation). To reduce the computational expenses, we calculate the effective solvation forces acting on the biomolecule by using advanced solvation force extrapolation (ASFE) at inner time steps while converging the 3D-RISM-KH integral equations only at large outer time steps. The idea of ASFE consists in developing a discrete non-Eckart rotational transformation of atomic coordinates that minimizes the distances between the atomic positions of the biomolecule at different time moments. The effective solvation forces for the biomolecule in a current conformation at an inner time step are then extrapolated in the transformed subspace of those at outer time steps by using a modified least square fit approach applied to a relatively small number of the best force-coordinate pairs. The latter are selected from an extended set collecting the effective solvation forces obtained from 3D-RISM-KH at outer time steps over a broad time interval. The MTS-MD integration with effective solvation forces obtained by converging 3D-RISM-KH at outer time steps and applying ASFE at inner time steps is stabilized by employing the optimized isokinetic Nosé-Hoover chain (OIN) ensemble. Compared to the previous extrapolation schemes used in combination with the Langevin thermostat, the ASFE approach substantially improves the accuracy of evaluation of effective solvation forces and in combination with the OIN thermostat enables a dramatic increase of outer time steps. We demonstrate on a fully flexible model of alanine dipeptide in aqueous solution that the MTS-MD/OIN/ASFE/3D-RISM-KH multiscale method of molecular dynamics steered by effective solvation forces allows huge outer time steps up to tens of picoseconds without affecting the equilibrium and conformational properties, and thus provides a 100- to 500-fold effective speedup in comparison to conventional MD with explicit solvent. With the statistical-mechanical 3D-RISM-KH account for effective solvation forces, the method provides efficient sampling of biomolecular processes with slow and/or rare solvation events such as conformational transitions of hydrated alanine dipeptide with the mean life times ranging from 30 ps up to 10 ns for “flip-flop” conformations, and is particularly beneficial for biomolecular systems with exchange and localization of solvent and ions, ligand binding, and molecular recognition.

Description: Unimolecular decay of sample ions imposes a limit on the usable laser fluence in matrix-assisted laser desorption/ionization (MALDI) ion sources. Traditionally, some modest degree of collisional sample ion cooling has been achieved by connecting MALDI ion sources directly to gas-filled radio frequency (RF) multipoles. It was also discovered in the early 1990s that gas-filled RF multipoles exhibit increased ion transmission efficiency due to collisional ion focusing effects. This unexpected experimental finding was later supported by elementary Monte Carlo simulations. Both experiments and simulations assumed a resting background gas with typical pressures of the order of 1 Pa. However, considerable additional improvements can be achieved if laser desorbed sample ions are introduced immediately after desorption, still within the ion source, in an axisymmetric rarefied supersonic gas jet with peak pressure of the order of 100 Pa and flow velocities 〉300 m/s, and under weak electric fields. We describe here the design principle and report performance data of an ion source coined “MALDI-2,” which incorporates elements of both rarefied aerodynamics and particle optics. Such a design allows superb suppression of metastable fragmentation due to rapid collisional cooling in

Description: The glycoprotein gp41 from the Human Immunodeficiency Virus type 1 (HIV-1) has an amino acid sequence enriched in tryptophan residues, the so-called gp41W peptide (i.e., KWASLWNWFNITNWLWYIK) and plays a crucial role in HIV-1 host cell infection. Using the coupling of Second Harmonic Generation targeting the tryptophan residues with lateral surface tension measurements, we investigate the interaction of gp41W with a neat air/water and a lipid/water interfaces. At the air/water interface, gp41W presents a well-defined orientation and this orientation is strongly modified at the lipid/water interface, depending on the surface pressure. These results show that this strategy is well suited to monitor tryptophan containing α-helices orientation at lipid/water interfaces.

Description: RNA folding kinetics is directly tied to RNA biological functions. We introduce here a new approach for predicting the folding kinetics of RNA secondary structure with pseudoknots. This approach is based on our previous established helix-based method for predicting the folding kinetics of RNA secondary structure. In this approach, the transition rates for an elementary step: (1) formation, (2) disruption of a helix stem, and (3) helix formation with concomitant partial melting of an incompatible helix, are calculated with the free energy landscape. The folding kinetics of the Hepatitis delta virus (HDV) ribozyme and the mutated sequences are studied with this method. The folding pathways are identified by recursive searching the states with high net flux-in(out) population starting from the native state. The theory results are in good agreement with that of the experiments. The results indicate that the bi-phasic folding kinetics for the wt HDV sequence is ascribed to the kinetic partitioning mechanism: Part of the population will quickly fold to the native state along the fast pathway, while another part of the population will fold along the slow pathway, in which the population is trapped in a non-native state. Single mutation not only changes the folding rate but also the folding pathway.

Description: Stick-spectrum expressions for electronic two-dimensional (2D) photon-echo (PE) signal of a generic multi-level system are presented and employed to interrelate oscillations in individual peaks of 2D PE signal and the underlying properties (eigenstates and coherent dynamics) of excitonic or vibronic systems. When focusing on the identification of the origin of oscillations in the rephasing part of 2D PE it is found, in particular, that multiple frequencies in the evolution of the individual peaks do not necessarily directly reflect the underlying system dynamics. They may originate from the excited-state absorption contribution to the signal, or arise due to multi-level vibrational structure of the electronic ground state, and represent a superposition of system frequencies, while the latter may evolve independently. The analytical stick-spectrum predictions are verified and illustrated by numerical calculations of 2D PE signals of an excitonic trimer and of a displaced harmonic oscillator with unequal vibrational frequencies in the two electronic states. The excitonic trimer is the smallest excitonic oligomer where excited-state absorption may represent a superposition of excited-state coherences and significantly influence the phase of the observed oscillations. The displaced oscillator is used to distinguish between the frequencies of the ground-state and of the excited-state manifolds, and to demonstrate how the location of a cross peak in 2D pattern of the PE signal “predetermines” its oscillatory behavior. Although the considered models are kept as simple as possible for clarity, the stick-spectrum analysis provides a solid general basis for interpretation of oscillatory signatures in electronic 2D PE signals of much more complex systems with multi-level character of the electronic states.

Description: An intrinsically disordered protein (IDP) lacks a stable three-dimensional structure, while it folds into a specific structure when it binds to a target molecule. In some IDP-target complexes, not all target binding surfaces are exposed on the outside, and intermediate states are observed in their binding processes. We consider that stepwise target recognition via intermediate states is a characteristic of IDP binding to targets with “hidden” binding sites. To investigate IDP binding to hidden target binding sites, we constructed an IDP lattice model based on the HP model. In our model, the IDP is modeled as a chain and the target is modeled as a highly coarse-grained object. We introduced motion and internal interactions to the target to hide its binding sites. In the case of unhidden binding sites, a two-state transition between the free states and a bound state is observed, and we consider that this represents coupled folding and binding. Introducing hidden binding sites, we found an intermediate bound state in which the IDP forms various structures to temporarily stabilize the complex. The intermediate state provides a scaffold for the IDP to access the hidden binding site. We call this process multiform binding. We conclude that structural flexibility of IDPs enables them to access hidden binding sites and this is a functional advantage of IDPs.

Description: We developed in recent years the two-body (protein and probe) coupled-rotator slowly relaxing local structure (SRLS) approach for elucidating protein dynamics from NMR spin relaxation. So far we used as descriptors the set of physical parameters that enter the SRLS model. They include the global (protein-related) diffusion tensor, D 1 , the local (probe-related) diffusion tensor, D 2 , and the local coupling/ordering potential, u . As common in analyzes based on mesoscopic dynamic models, these parameters have been determined with data-fitting techniques. In this study, we describe structural dynamics in terms of the eigenmodes comprising the SRLS time correlation functions (TCFs) generated by using the best-fit parameters as input to the Smoluchowski equation. An eigenmode is a weighted exponential with decay constant given by an eigenvalue of the Smoluchowski operator, and weighting factor determined by the corresponding eigenvector. Obviously, both quantities depend on the SRLS parameters as determined by the SRLS model. Unlike the set of best-fit parameters, the eigenmodes represent patterns of motion of the probe-protein system. The following new information is obtained for the typical probe, the 15 N− 1 H bond. Two eigenmodes, associated with the protein and the probe, dominate when the time scale separation is large (i.e., D 2 ≫ D 1 ), the tensorial properties are simple, and the local potential is either very strong or very weak. When the potential exceeds these limits while the remaining conditions are preserved, new eigenmodes arise. The multi-exponentiality of the TCFs is associated in this case with the restricted nature of the local motion. When the time scale separation is no longer large, the rotational degrees of freedom of the protein and the probe become statistically dependent (coupled dynamically). The multi-exponentiality of the TCFs is associated in this case with the restricted nature of both the local and the global motion. The effects of local diffusion axiality, potential strength, and extent of mode-coupling on the eigenmode setup are investigated. We detect largely global motional or largely local motional eigenmodes. In addition, we detect mixed eigenmodes associated with correlated/prograde or anti-correlated/retrograde rotations of the global ( D 1 ) and local ( D 2 ) motional modes. The eigenmode paradigm is applied to N−H bond dynamics in the β-sheet residue K19, and the α-helix residue A34, of the third immunoglobulin-binding domain of streptococcal protein G. The largest contribution to the SRLS TCFs is made by mixed anti-correlated D 1 and D 2 eigenmodes. The next largest contribution is made by D 1 -dominated eigenmodes. Eigenmodes dominated by the local motion contribute appreciably to A34 and marginally to K19. Correlated D 1 and D 2 eigenmodes contribute exclusively to K19 and do not contribute above 1% to A34. The differences between K19 and A34 are delineated and rationalized in terms of the best-fit SRLS parameters and mode-mixing. It may be concluded that eigenmode analysis is complementary and supplementary to data-fitting-based analysis.

Description: We propose a method for computing the activation barrier for chemical reactions involving molecules subjected to mechanical stress. The method avoids reactant and transition-state saddle optimizations at every force by, instead, solving the differential equations governing the force dependence of the critical points (i.e., minima and saddles) on the system's potential energy surface (PES). As a result, only zero-force geometry optimization (or, more generally, optimization performed at a single force value) is required by the method. In many cases, minima and transition-state saddles only exist within a range of forces and disappear beyond a certain critical point. Our method identifies such force-induced instabilities as points at which one of the Hessian eigenvalues vanishes. We elucidate the nature of those instabilities as fold and cusp catastrophes, where two or three critical points on the force-modified PES coalesce, and provide a classification of various physically distinct instability scenarios, each illustrated with a concrete chemical example.

Description: A matrix isolation study of the infrared spectra and structure of anethole (1-methoxy-4-(1-propenyl)benzene) has been carried out, showing the presence of two E conformers (AE1, AE2) of the molecule in the as-deposited matrices. Irradiation using ultraviolet-tunable laser light at 308–307 nm induced conformationally selective phototransformations of these forms into two less stable Z conformers (AZ1, AZ2). The back reactions were also detected upon irradiation at 301 nm. On the whole, the obtained results allow for full assignment of the infrared spectra of all the four experimentally observed anethole isomers and showed that the narrowband UV-induced E-Z photoisomerization is an efficient and selective way to interconvert the two isomers of anethole into each other, with conformational discrimination. Photolysis of anethole was observed as well, with initial methoxyl O–C bond cleavage and formation of CH 3 and p -propenylphenoxy (AR) radicals, followed by radical recombination to form 2-methyl-4-propenyl-2,4-cyclohexadienone, which subsequently undergoes ring-opening generating several conformers of long-chain conjugated ketenes. Interpretation of the experimental observations was supported by density functional theory (B3LYP and B2PLYD) calculations.

Description: We investigated molecular motions in the 0.3–350 ps time range of D 2 O-hydrated bilayers of 1-palmitoyl-oleoyl-sn-glycero-phosphocholine and 1,2-dimyristoyl-sn-glycero-phosphocholine in the liquid phase by quasielastic neutron scattering. Model analysis of sets of spectra covering scale lengths from 4.8 to 30 Å revealed the presence of three types of motion taking place on well-separated time scales: (i) slow diffusion of the whole phospholipid molecules in a confined cylindrical region; (ii) conformational motion of the phospholipid chains; and (iii) fast uniaxial rotation of the hydrogen atoms around their carbon atoms. Based on theoretical models for the hydrogen dynamics in phospholipids, the spatial extent of these motions was analysed in detail and the results were compared with existing literature data. The complex dynamics of protons was described in terms of elemental dynamical processes involving different parts of the phospholipid chain on whose motions the hydrogen atoms ride.

Description: Many proteins undergo a conformational transition upon binding to their cognate binding partner, with intrinsically disordered proteins (IDPs) providing an extreme example in which a folding transition occurs. However, it is often not clear whether this occurs via an “induced fit” or “conformational selection” mechanism, or via some intermediate scenario. In the first case, transient encounters with the binding partner favour transitions to the bound structure before the two proteins dissociate, while in the second the bound structure must be selected from a subset of unbound structures which are in the correct state for binding, because transient encounters of the incorrect conformation with the binding partner are most likely to result in dissociation. A particularly interesting situation involves those intrinsically disordered proteins which can bind to different binding partners in different conformations. We have devised a multi-state coarse-grained simulation model which is able to capture the binding of IDPs in alternate conformations, and by applying it to the binding of nuclear coactivator binding domain (NCBD) to either ACTR or IRF-3 we are able to determine the binding mechanism. By all measures, the binding of NCBD to either binding partner appears to occur via an induced fit mechanism. Nonetheless, we also show how a scenario closer to conformational selection could arise by choosing an alternative non-binding structure for NCBD.

Description: Many problems in biology, chemistry, and materials science require knowledge of saddle points on free energy surfaces. These saddle points act as transition states and are the bottlenecks for transitions of the system between different metastable states. For simple systems in which the free energy depends on a few variables, the free energy surface can be precomputed, and saddle points can then be found using existing techniques. For complex systems, where the free energy depends on many degrees of freedom, this is not feasible. In this paper, we develop an algorithm for finding the saddle points on a high-dimensional free energy surface “on-the-fly” without requiring a priori knowledge the free energy function itself. This is done by using the general strategy of the heterogeneous multi-scale method by applying a macro-scale solver, here the gentlest ascent dynamics algorithm, with the needed force and Hessian values computed on-the-fly using a micro-scale model such as molecular dynamics. The algorithm is capable of dealing with problems involving many coarse-grained variables. The utility of the algorithm is illustrated by studying the saddle points associated with (a) the isomerization transition of the alanine dipeptide using two coarse-grained variables, specifically the Ramachandran dihedral angles, and (b) the beta-hairpin structure of the alanine decamer using 20 coarse-grained variables, specifically the full set of Ramachandran angle pairs associated with each residue. For the alanine decamer, we obtain a detailed network showing the connectivity of the minima obtained and the saddle-point structures that connect them, which provides a way to visualize the gross features of the high-dimensional surface.

Description: If the molecules of a given solvent possess significant quadrupolar moment, the macroscopic Maxwell equations must involve the contribution of the density of the quadrupolar moment to the electric displacement field. This modifies the Poisson-Boltzmann equation and all consequences from it. In this work, the structure of the diffuse atmosphere around an ion dissolved in quadrupolarizable medium is analyzed by solving the quadrupolar variant of the Coulomb-Ampere's law of electrostatics. The results are compared to the classical Debye-Hückel theory. The quadrupolar version of the Debye-Hückel potential of a point charge is finite even in r = 0. The ion-quadrupole interaction yields a significant expansion of the diffuse atmosphere of the ion and, thus, it decreases the Debye-Hückel energy. In addition, since the dielectric permittivity of the electrolyte solutions depends strongly on concentration, the Born energy of the dissolved ions alters with concentration, which has a considerable contribution to the activity coefficient γ ± known as the self-salting-out effect. The quadrupolarizability of the medium damps strongly the self-salting-out of the electrolyte, and thus it affects additionally γ ± . Comparison with experimental data for γ ± for various electrolytes allows for the estimation of the quadrupolar length of water: L Q ≈ 2 Å, in good agreement with previous assessments. The effect of quadrupolarizability is especially important in non-aqueous solutions. Data for the activity of NaBr in methanol is used to determine the quadrupolarizability of methanol with good accuracy.

Description: The Hybrid Monte Carlo method offers a rigorous and potentially efficient approach to the simulation of dense systems, by combining numerical integration of Newton's equations of motion with a Metropolis accept-or-reject step. The Metropolis step corrects for sampling errors caused by the discretization of the equations of motion. The integration is usually performed using a uniform step size. Here, we present simulations of the Lennard-Jones system showing that the use of smaller time steps in the tails of each integration trajectory can reduce errors in energy. The acceptance rate is 10–15 percentage points higher in these runs, compared to simulations with the same trajectory length and the same number of integration steps but a uniform step size. We observe similar effects for the harmonic oscillator and a coarse-grained peptide model, indicating generality of the approach.

Description: Charge transfer in a hydrogen-bonded N -methylacetamide(H 2 O) 3 system is obtained from ωB97X-D/6-31++G** and CHelpG atomic charge calculations of individual peptide-water interactions as well as that of the entire complex. In the latter, the electron transfer to water is 0.19 e , influenced primarily by the hydrogen bonds to the C=O group. The values of such charge transfer are paralleled by the corresponding intrinsic hydrogen-bond energies. These results support the desirability of incorporating charge transfer in molecular mechanics energy functions.

Description: Dynamical decoupling, a generalization of the original NMR spin-echo sequence, is becoming increasingly relevant as a tool for reducing decoherence in quantum systems. Such sequences apply non-equidistant refocusing pulses for optimizing the coupling between systems, and environmental fluctuations characterized by a given noise spectrum. One such sequence, dubbed Selective Dynamical Recoupling (SDR) [P. E. S. Smith, G. Bensky, G. A. Álvarez, G. Kurizki, and L. Frydman, Proc. Natl. Acad. Sci.109, 5958 (2012)], allows one to coherently reintroduce diffusion decoherence effects driven by fluctuations arising from restricted molecular diffusion [G. A. Álvarez, N. Shemesh, and L. Frydman, Phys. Rev. Lett.111, 080404 (2013)]. The fully-refocused, constant-time, and constant-number-of-pulses nature of SDR also allows one to filter out “intrinsic” T 1 and T 2 weightings, as well as pulse errors acting as additional sources of decoherence. This article explores such features when the fluctuations are now driven by unrestricted molecular diffusion. In particular, we show that diffusion-driven SDR can be exploited to investigate the decoherence arising from the frequency fluctuations imposed by internal gradients. As a result, SDR presents a unique way of probing and characterizing these internal magnetic fields, given an a priori known free diffusion coefficient. This has important implications in studies of structured systems, including porous media and live tissues, where the internal gradients may serve as fingerprints for the system's composition or structure. The principles of this method, along with full analytical solutions for the unrestricted diffusion-driven modulation of the SDR signal, are presented. The potential of this approach is demonstrated with the generation of a novel source of MRI contrast, based on the background gradients active in an ex vivo mouse brain. Additional features and limitations of this new method are discussed.

Description: The three-site hops of methyl groups are usually used as an approximation of the mechanistic description of motions responsible for the longitudinal NMR relaxation. Distinguishing between three-site hops and a more realistic mechanism of diffusion in a potential requires extended experimental and computational analysis. In order to achieve this goal, in this work the restricted diffusion is decomposed into two independent modes, namely, the jumps between potential wells and intra-well fluctuations, assuming time scale separation between these modes. This approach allows us to explain the rise in the theoretical value of T 1 minimum for the restricted diffusion mechanism compared with the three-site hops mechanism via rescaling the three-site hops correlation function by the order parameter of intra-well motions. The main result of the paper is that, in general, intra-well dynamics can be visible in NMR even in the limit of large barrier heights in contrast to the common view that this limit converges to the three-site hops mechanism. Based on a previously collected detailed set of deuteron NMR relaxation and spectral data in the villin headpiece subdomain protein over a wide temperature range of 300–31 K, we are then able to conclude that the mechanism of diffusion in the threefold potential is likely to be the main source of the dynamics in this system.

Description: The fundamental processes of biological development are governed by multiple signaling molecules that create non-uniform concentration profiles known as morphogen gradients. It is widely believed that the establishment of morphogen gradients is a result of complex processes that involve diffusion and degradation of locally produced signaling molecules. We developed a multi-dimensional discrete-state stochastic approach for investigating the corresponding reaction-diffusion models. It provided a full analytical description for stationary profiles and for important dynamic properties such as local accumulation times, variances, and mean first-passage times. The role of discreteness in developing of morphogen gradients is analyzed by comparing with available continuum descriptions. It is found that the continuum models prediction about multiple time scales near the source region in two-dimensional and three-dimensional systems is not supported in our analysis. Using ideas that view the degradation process as an effective potential, the effect of dimensionality on establishment of morphogen gradients is also discussed. In addition, we investigated how these reaction-diffusion processes are modified with changing the size of the source region.

Description: We investigated the excitation modes of the light-harvesting protein phycocyanin (PC) from Thermosynechococcus vulcanus in the crystalline state using UV and near-infrared Raman spectroscopy. The spectra revealed the absence of a hydrogen out-of-plane wagging (HOOP) mode in the PC trimer, which suggests that the HOOP mode is activated in the intact PC rod, while it is not active in the PC trimer. Furthermore, in the PC trimer an intense mode at 984 cm −1 is assigned to the C–C stretching vibration while the mode at 454 cm −1 is likely due to ethyl group torsion. In contrast, in the similar chromophore phytochromobilin the C 5,10,15 -D wag mode at 622 cm −1 does not come from a downshift of the HOOP. Additionally, the absence of modes between 1200 and 1300 cm −1 rules out functional monomerization. A correlation between phycocyanobilin (PCB) and phycoerythrobilin (PEB) suggests that the PCB cofactors of the PC trimer appear in a conformation similar to that of PEB. The conformation of the PC rod is consistent with that of the allophycocyanin (APC) trimer, and thus excitonic flow is facilitated between these two independent light-harvesting compounds. This excitonic flow from the PC rod to APC appears to be modulated by the vibration channels during HOOP wagging, C = C stretching, and the N–H rocking in-plan vibration.

Description: The first hydration shell of the protonated glycine is built up using Monte Carlo multiple minimum conformational search analysis with the MMFFs force field. The potential energy surfaces of the protonated glycine and its hydration complexes with up to eight water molecules have been scanned and the energy-minimized structures are predicted using the ab initio calculations. First, three favorable structures of protonated glycine were determined, and the micro-hydration processes showed that water can significantly stabilize the unstable conformers, and then their first hydration shells were established. Finally, we found that seven water molecules are required to fully hydrate the first hydration shell for the most stable conformer of protonated glycine. In order to analyse the hydration process, the dominant hydration sites located around the ammonium and carboxyl groups are studied carefully and systemically. The results indicate that, water molecules hydrate the protonated glycine in an alternative dynamic hydration process which is driven by the competition between different hydration sites. The first three water molecules are strongly attached by the ammonium group, while only the fourth water molecule is attached by the carboxyl group in the ultimate first hydration shell of the protonated glycine. In addition, the first hydration shell model has predicted most identical structures and a reasonable accord in hydration energy and vibrational frequencies of the most stable conformer with the conductor-like polarizable continuum model.

Description: The mechanism by which conformational changes, particularly folding and unfolding, occur in proteins and other biopolymers has been widely discussed in the literature. Molecular dynamics (MD) simulations of protein folding present a formidable challenge since these conformational changes occur on a time scale much longer than what can be afforded at the current level of computational technology. Transition state (TS) theory offers a more economic description of kinetic properties of a reaction system by relating them to the properties of the TS, or for flexible systems, the TS ensemble (TSE). The application of TS theory to protein folding is limited by ambiguity in the definition of the TSE for this process. We propose to identify the TSE for conformational changes in flexible systems by comparison of its experimentally determined volumetric property, known as the volume of activation, to the structure-specific volume profile of the process calculated using MD. We illustrate this approach by its successful application to unfolding of a model chain system.

Description: We study the parameter sensitivity of hetero-polymeric DNA within the purview of DNA breathing dynamics. The degree of correlation between the mean bubble size and the model parameters is estimated for this purpose for three different DNA sequences. The analysis leads us to a better understanding of the sequence dependent nature of the breathing dynamics of hetero-polymeric DNA. Out of the 14 model parameters for DNA stability in the statistical Poland-Scheraga approach, the hydrogen bond interaction ε h b ( AT ) for an AT base pair and the ring factor ξ turn out to be the most sensitive parameters. In addition, the stacking interaction ε s t ( TA - TA ) for an TA - TA nearest neighbor pair of base-pairs is found to be the most sensitive one among all stacking interactions. Moreover, we also establish that the nature of stacking interaction has a deciding effect on the DNA breathing dynamics, not the number of times a particular stacking interaction appears in a sequence. We show that the sensitivity analysis can be used as an effective measure to guide a stochastic optimization technique to find the kinetic rate constants related to the dynamics as opposed to the case where the rate constants are measured using the conventional unbiased way of optimization.

Description: Many molecules exhibit multiple conformers that often easily interconvert under thermal conditions. Therefore, single conformations are difficult to isolate which renders the study of their distinct chemical reactivities challenging. We have recently reported a new experimental method for the characterization of conformer-specific effects in chemical reactions [Y.-P. Chang, K. Długołęcki, J. Küpper, D. Rösch, D. Wild, and S. Willitsch, “Specific chemical reactivities of spatially separated 3-aminophenol conformers with cold Ca + ions,” Science342, 98–101 (2013)]. Different conformers are spatially separated using inhomogeneous electric fields and reacted with a Coulomb crystal of cold, spatially localized ions in a trap. As a first application, we studied reactions between the two conformers of 3-aminophenol and Ca + . We observed a twofold larger rate constant for the cis compared to the trans conformer which was rationalized in terms of the differences in the long-range ion-molecule interactions. The present article provides a detailed description of the new method and a full account of the experimental results as well as the accompanying theoretical calculations.

Description: We investigate the low density behaviour of fluids that interact through a short-ranged attraction together with a long-ranged repulsion (SALR potential) by developing a molecular thermodynamic model. The SALR potential is a model of effective solute interactions where the solvent degrees of freedom are integrated-out. For this system, we find that clusters form for a range of interaction parameters where attractive and repulsive interactions nearly balance, similar to micelle formation in aqueous surfactant solutions. We focus on systems for which equilibrium behaviour and liquid-like clusters (i.e., droplets) are expected, and find in addition a novel coexistence between a low density cluster phase and a high density cluster phase within a very narrow range of parameters. Moreover, a simple formula for the average cluster size is developed. Based on this formula, we propose a non-classical crystal nucleation pathway whereby macroscopic crystals are formed via crystal nucleation within microscopic precursor droplets. We also perform large-scale Monte Carlo simulations, which demonstrate that the cluster fluid phase is thermodynamically stable for this system.

Description: A theoretical framework based on a generalized Langevin equation (GLE) with fractional Gaussian noise (fGn) and a power-law memory kernel is presented to describe the non-exponential kinetics of the unfolding of a single poly-ubiquitin molecule under a constant force [T.-L. Kuo, S. Garcia-Manyes, J. Li, I. Barel, H. Lu, B. J. Berne, M. Urbakh, J. Klafter, and J. M. Fernández, Proc. Natl. Acad. Sci. U.S.A.107, 11336 (2010)]. Such a GLE-fGn strategy is made on the basis that the pulling coordinate variable x undergoes subdiffusion, usually resulting from conformational fluctuations, over a one-dimensional force-modified free-energy surface U ( x , F ). By using the Kramers’ rate theory, we have obtained analytical formulae for the time-dependent rate coefficient k ( t , F ), the survival probability S ( t , F ) as well as the waiting time distribution function f ( t , F ) as functions of time t and force F . We find that our results can fit the experimental data of f ( t , F ) perfectly in the whole time range with a power-law exponent γ = 1/2, the characteristic of typical anomalous subdiffusion. In addition, the fitting of the survival probabilities for different forces facilitates us to reach rather reasonable estimations for intrinsic properties of the system, such as the free-energy barrier and the distance between the native conformation and the transition state conformation along the reaction coordinate, which are in good agreements with molecular dynamics simulations in the literatures. Although static disorder has been implicated in the original work of Kuo et al. , our work suggests a sound and plausible alternative interpretation for the non-exponential kinetics in the stretching of poly-ubiquitin molecules, associated with dynamic disorder.

Description: A powerful conformational sampling method for accelerating structural transitions of proteins, “Fluctuation Flooding Method (FFM),” is proposed. In FFM, cycles of the following steps enhance the transitions: (i) extractions of largely fluctuating snapshots along anisotropic modes obtained from trajectories of multiple independent molecular dynamics (MD) simulations and (ii) conformational re-sampling of the snapshots via re-generations of initial velocities when re-starting MD simulations. In an application to bacteriophage T4 lysozyme, FFM successfully accelerated the open-closed transition with the 6 ns simulation starting solely from the open state, although the 1- μ s canonical MD simulation failed to sample such a rare event.

Description: Results of optical absorption measurements are presented together with calculated structural, electronic, and optical properties for the anhydrous monoclinic L-asparagine crystal. Density functional theory (DFT) within the generalized gradient approximation (GGA) including dispersion effects (TS, Grimme) was employed to perform the calculations. The optical absorption measurements revealed that the anhydrous monoclinic L-asparagine crystal is a wide band gap material with 4.95 eV main gap energy. DFT-GGA+TS simulations, on the other hand, produced structural parameters in very good agreement with X-ray data. The lattice parameter differences Δ a , Δ b , Δ c between theory and experiment were as small as 0.020, 0.051, and 0.022 Å, respectively. The calculated band gap energy is smaller than the experimental data by about 15%, with a 4.23 eV indirect band gap corresponding to Z → Γ and Z → β transitions. Three other indirect band gaps of 4.30 eV, 4.32 eV, and 4.36 eV are assigned to α3 → Γ, α1 → Γ, and α2 → Γ transitions, respectively. Δ-sol computations, on the other hand, predict a main band gap of 5.00 eV, just 50 meV above the experimental value. Electronic wavefunctions mainly originating from O 2 p –carboxyl, C 2 p –side chain, and C 2 p –carboxyl orbitals contribute most significantly to the highest valence and lowest conduction energy bands, respectively. By varying the lattice parameters from their converged equilibrium values, we show that the unit cell is less stiff along the b direction than for the a and c directions. Effective mass calculations suggest that hole transport behavior is more anisotropic than electron transport, but the mass values allow for some charge mobility except along a direction perpendicular to the molecular layers of L-asparagine which form the crystal, so anhydrous monoclinic L-asparagine crystals could behave as wide gap semiconductors. Finally, the calculations point to a high degree of optical anisotropy for the absorption and complex dielectric function, with more structured curves for incident light polarized along the 100 and 101 directions.

Description: The self-assembly of biological and synthetic nanostructures commonly proceeds via intermediate states. In living systems in particular, the intermediates have the capacity to tilt the balance between functional and potentially fatal behavior. This work develops a statistical mechanical treatment of conformational dynamics through an intermediate under a variable force. An analytical solution is derived for the key experimentally measurable quantity—the distribution of forces at which a conformational transition occurs. The solution reveals rich kinetics over a broad range of parameters and enables one to locate the intermediate and extract the activation barriers and rate constants.

Description: We investigate the effectiveness of charge patterns along a nanopore on translocation dynamics of a flexible polyelectrolyte. We perform a three dimensional Langevin dynamics simulation of a uniformly charged flexible polyelectrolyte translocating under uniform external electric field through a solid-state nanopore. We maintain the total charge along the pore to be constant, while varying its distribution by placing alternate charged and uncharged sections of different lengths along the pore length. Longest average translocation time is observed for a pattern corresponding to an optimum section length, with a major delay in the translocation time during the pore ejection stage. This optimum section length is independent of lengths of polyelectrolyte and pore within the range studied. A theory based on the Fokker-Planck formalism is found to successfully describe the observed trends with reasonable quantitative agreement.

Description: Using the helix-coil transitions of alanine pentapeptide as an illustrative example, we demonstrate the use of diffusion maps in the analysis of molecular dynamics simulation trajectories. Diffusion maps and other nonlinear data-mining techniques provide powerful tools to visualize the distribution of structures in conformation space. The resulting low-dimensional representations help in partitioning conformation space, and in constructing Markov state models that capture the conformational dynamics. In an initial step, we use diffusion maps to reduce the dimensionality of the conformational dynamics of Ala5. The resulting pretreated data are then used in a clustering step. The identified clusters show excellent overlap with clusters obtained previously by using the backbone dihedral angles as input, with small—but nontrivial—differences reflecting torsional degrees of freedom ignored in the earlier approach. We then construct a Markov state model describing the conformational dynamics in terms of a discrete-time random walk between the clusters. We show that by combining fuzzy C-means clustering with a transition-based assignment of states, we can construct robust Markov state models. This state-assignment procedure suppresses short-time memory effects that result from the non-Markovianity of the dynamics projected onto the space of clusters. In a comparison with previous work, we demonstrate how manifold learning techniques may complement and enhance informed intuition commonly used to construct reduced descriptions of the dynamics in molecular conformation space.

Description: We have simulated the transport properties of a uniformly charged flexible polymer chain and its counterions confined inside cylindrical nanopores under an external electric field. The hydrodynamic interaction is treated by describing the solvent molecules explicitly with the multiparticle collision dynamics method. The chain consisting of charged monomers and the counterions interact electrostatically with themselves and with the external electric field. We find rich behavior of the counterions around the polymer under confinement in the presence of the external electric field. The mobility of the counterions is heterogeneous depending on their location relative to the polymer. The adsorption isotherm of the counterions on the polymer depends nonlinearly on the electric field. As a result, the effective charge of the polymer exhibits a sigmoidal dependence on the electric field. This in turn leads to a nascent nonlinearity in the chain stretching and electrophoretic mobility of the polymer in terms of their dependence on the electric field. The product of the electric field and the effective polymer charge is found to be the key variable to unify our simulation data for various polymer lengths. Chain extension and the electrophoretic mobility show sigmoidal dependence on the electric field, with crossovers from the linear response regime to the nonlinear regime and then to the saturation regime. The mobility of adsorbed counterions is nonmonotonic with the electric field. For weaker and moderate fields, the adsorbed counterions move with the polymer and at higher fields they move opposite to the polymer's direction. We find that the effective charge and the mobility of the polymer decrease with a decrease in the pore radius.

Description: Atomistic molecular dynamics simulation of an aqueous solution of the small protein HP-36 has been carried out with explicit solvent at room temperature. Efforts have been made to explore the influence of the protein on the relative packing and ordering of water molecules around its secondary structures, namely, three α-helices. The calculations reveal that the inhomogeneous water ordering and density distributions around the helices are correlated with their relative hydrophobicity. Importantly, we have identified the existence of a narrow relatively dehydrated region containing randomly organized “quasi-free” water molecules beyond the first layer of “bound” waters at the protein surface. These water molecules with relatively weaker binding energies form the transition state separating the “bound” and “free” water molecules at the interface. Further, increased contribution of solid-like caging motions of water molecules around the protein is found to be responsible for reduced fluidity of the hydration layer. Interestingly, we notice that the hydration layer of helix-3 is more fluidic with relatively higher entropy as compared to the hydration layers of the other two helical segments. Such characteristics of helix-3 hydration layer correlate well with the activity of HP-36, as helix-3 contains the active site of the protein.

Description: Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory (“one-end momentum reversal”). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory (“symmetric two-ends momentum reversal”), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.

Description: While the theoretical description of population transfer subsequent to electronic excitation in combination with a line shape function description of vibrational dynamics in the context of 2D-spectroscopy is well-developed under the assumption of different timescales of population transfer and fluctuation dynamics, the treatment of the interplay between both kinds of processes lacks a comprehensive description. To bridge this gap, we use the cumulant expansion approach to derive response functions, which account for fluctuation dynamics and population transfer simultaneously. We compare 2D-spectra of a model system under different assumptions about correlations between fluctuations and point out under which conditions a simplified treatment is justified. Our study shows that population transfer and dissipative fluctuation dynamics cannot be described independent of each other in general. Advantages and limitations of the proposed calculation method and its compatibility with the modified Redfield description are discussed.

Description: Electrostatic forces enormously impact the structure, interactions, and function of biomolecules. We perform all-atom molecular dynamics simulations for 5 proteins and 5 RNAs to determine the dependence on ionic strength of the ion and water charge distributions surrounding the biomolecules, as well as the contributions of ions to the electrostatic free energy of interaction between the biomolecule and the surrounding salt solution (for a total of 40 different biomolecule/solvent combinations). Although water provides the dominant contribution to the charge density distribution and to the electrostatic potential even in 1M NaCl solutions, the contributions of water molecules and of ions to the total electrostatic interaction free energy with the solvated biomolecule are comparable. The electrostatic biomolecule/solvent interaction energies and the total charge distribution exhibit a remarkable insensitivity to salt concentrations over a huge range of salt concentrations (20 mM to 1M NaCl). The electrostatic potentials near the biomolecule's surface obtained from the MD simulations differ markedly, as expected, from the potentials predicted by continuum dielectric models, even though the total electrostatic interaction free energies are within 11% of each other.

Description: We developed a statistical thermodynamic algorithm for analyzing solvent-induced folding/unfolding transitions of proteins. The energetics of protein transitions is governed by the interplay between the cavity formation contribution and the term reflecting direct solute-cosolvent interactions. The latter is viewed as an exchange reaction in which the binding of a cosolvent to a solute is accompanied by release of waters of hydration to the bulk. Our model clearly differentiates between the stoichiometric and non-stoichiometric interactions of solvent or co-solvent molecules with a solute. We analyzed the urea- and glycine betaine (GB)-induced conformational transitions of model proteins of varying size which are geometrically approximated by a sphere in their native state and a spherocylinder in their unfolded state. The free energy of cavity formation and its changes accompanying protein transitions were computed based on the concepts of scaled particle theory. The free energy of direct solute-cosolvent interactions were analyzed using empirical parameters previously determined for urea and GB interactions with low molecular weight model compounds. Our computations correctly capture the mode of action of urea and GB and yield realistic numbers for (∂ΔG°/∂a 3 ) T,P which are related to the m-values of protein denaturation. Urea is characterized by negative values of (∂ΔG°/∂a 3 ) T,P within the entire range of urea concentrations analyzed. At concentrations below ∼1 M, GB exhibits positive values of (∂ΔG°/∂a 3 ) T,P which turn positive at higher GB concentrations. The balance between the thermodynamic contributions of cavity formation and direct solute-cosolvent interactions that, ultimately, defines the mode of cosolvent action is extremely subtle. A 20% increase or decrease in the equilibrium constant for solute-cosolvent binding may change the sign of (∂ΔG°/∂a 3 ) T,P thereby altering the mode of cosolvent action (stabilizing to destabilizing or vice versa ).

Description: The structural stability and function of biomolecules is strongly influenced by the dynamics and hydrogen bonding of interfacial water. Understanding and characterizing the dynamics of these water molecules require a surface-sensitive technique such as two-dimensional vibrational sum-frequency generation (2DSFG) spectroscopy. We have combined theoretical 2DSFG calculations with molecular dynamics simulations in order to investigate the dynamics of water near different lipid and surfactant monolayer surfaces. We show that 2DSFG can distinguish the dynamics of interfacial water as a function of the lipid charge and headgroup chemistry. The dynamics of water is slow compared to the bulk near water-zwitterionic and water-anionic interfaces due to conformational constraints on interfacial water imposed by strong phosphate-water hydrogen bonding. The dynamics of water is somewhat faster near water-cationic lipid interfaces as no such constraint is present. Using hydrogen bonding and rotational correlation functions, we characterize the dynamics of water as a function of the distance from the interface between water and zwitterionic lipids. We find that there is a transition from bulk-like to interface-like dynamics approximately 7 Å away from a zwitterionic phosphatidylcholine monolayer surface.

Description: We present experimental results on photofragmentation of cooled fragments issued from the photofragmentation of cold parent ions. The cooling of the daughter ions at a few K allows its characterization not only through its fragmentation pattern but also through its well resolved electronic spectroscopy. The proof of principle of the method is demonstrated on the photofragment resulting from C α –C β bond rupture in protonated tyrosine (TyrH + ). The analysis of the daughter ion (m/z 108) photofragmentation spectrum is in agreement with the proposed mechanism implying a proton transfer to the phenyl ring as the first step of the fragmentation mechanism of TyrH + .

Description: In this study, we analyze correlations of vibrational motion on the surface of a small globular protein and in its hydration shell. In contrast to single particle hydration water dynamics, which are perturbed by interactions with the protein solute only in the first few hydration layers, we find that correlated, collective motions extend into the surrounding solvent on a 10 Å length scale, specifically at far-infrared frequencies below 100 cm −1 . As a function of frequency, we analyze the distribution of correlated longitudinal motions in the three-dimensional environment of the protein solute, as well as in the vicinity of different protein-water interfaces. An anisotropic distribution of these correlations is observed, which is related to specific protein-water vibrations and interactions at the interfaces, as well as flexibilities of solvent exposed sites. Our results show that coupling of protein and water dynamics leaves a three-dimensional imprint in the collective dynamics of its hydration shell, and we discuss potential implications for biomolecular function, e.g., molecular recognition and binding, and the dynamical coupling of proteins to their native solvation environment.

Description: The long four-helix bundle antifreeze protein Maxi contains an unusual core for a globular protein. More than 400 ordered waters between the helices form a nano-pore of internal water about 150 Å long. Molecular dynamics simulations of hydrated Maxi were carried out using the CHARMM27 protein forcefield and the TIP3P water model. Solvation in the core and non-core first hydration shell was analyzed in terms of water-water H-bond distance-angle distributions. The core had an increased population of low-angle H-bonds between water pairs relative to bulk water. Enhancement of low angle H-bonds was particularly pronounced for water pairs at the interfaces between apolar and polar regions inside the protein core, characteristic of the anchored clathrate solvation structure seen previously in the ice-nuclei binding surfaces of type I, type III, and beta-helical antifreeze proteins. Anchored clathrate type solvation structure was not seen in the exterior solvation shell except around residues implicated in ice binding. Analysis of solvation dynamics using water residence times and diffusion constants showed that exterior solvation shell waters exchanged rapidly with bulk water, with no difference between ice-binding and non-binding residues. Core waters had about ten-fold slower diffusion than bulk water. Water residence times around core residues averaged about 8 ps, similar to those on the exterior surface, but they tended to exchange primarily with other core water, resulting in longer, 〉40 ps residence times within the core. Preferential exchange or diffusion of the water along the long axis of the water core of Maxi was not detected.

Description: The protein folding funnel paradigm suggests that folding and unfolding proceed as directed diffusion in a multidimensional free energy surface where a multitude of pathways can be traversed during the protein's sojourn from initial to final state. However, finding even a single pathway, with the detail chronicling of intermediates, is an arduous task. In this work we explore the free energy surface of unfolding pathway through umbrella sampling, for a small globular α-helical protein chicken-villin headpiece (HP-36) when the melting of secondary structures is induced by adding DMSO in aqueous solution. We find that the unfolding proceeds through the initial separation or melting of aggregated hydrophobic core that comprises of three phenylalanine residues (Phe7, Phe11, and Phe18). This separation is accompanied by simultaneous melting of the second helix. Unfolding is found to be a multistage process involving crossing of three consecutive minima and two barriers at the initial stage. At a molecular level, Phe18 is observed to reorient itself towards other hydrophobic grooves to stabilize the intermediate states. We identify the configuration of the intermediates and correlate the intermediates with those obtained in our previous works. We also give an estimate of the barriers for different transition states and observe the softening of the barriers with increasing DMSO concentration. We show that higher concentration of DMSO tunes the unfolding pathway by destabilizing the third minimum and stabilizing the second one, indicating the development of a solvent modified, less rugged pathway. The prime outcome of this work is the demonstration that mixed solvents can profoundly transform the nature of the energy landscape and induce unfolding via a modified route. A successful application of Kramer's rate equation correlating the free energy simulation results shows faster rate of unfolding with increasing DMSO concentration. This work perhaps presents the first systematic theoretical study of the effect of a chemical denaturant on the microscopic free energy surface and rates of unfolding of HP-36.

Description: Small open chemical systems, typically associated with far-from-equilibrium, nonlinear stochastic dynamics, offer the appropriate framework to elucidate biological phenomena at the cellular scale. Stochastic differential equations of Langevin-type are employed to establish the relation between the departure from equilibrium and the time cross-correlation functions of concentration fluctuations for chemical species susceptible to oscillate. Except in the immediate vicinity of the Hopf bifurcation, the results are in agreement with simulations of the chemical master equation but always differ from the prediction obtained for linear deterministic dynamics. In general, the magnitude of the asymmetry of time correlation functions definitely depends on the reaction flux circulating in an open system but also on the details of the nonlinearities of deterministic dynamics.

Description: In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.

Description: We propose a new exact stochastic rejection-based simulation algorithm for biochemical reactions and extend it to systems with delays. Our algorithm accelerates the simulation by pre-computing reaction propensity bounds to select the next reaction to perform. Exploiting such bounds, we are able to avoid recomputing propensities every time a (delayed) reaction is initiated or finished, as is typically necessary in standard approaches. Propensity updates in our approach are still performed, but only infrequently and limited for a small number of reactions, saving computation time and without sacrificing exactness. We evaluate the performance improvement of our algorithm by experimenting with concrete biological models.

Description: We show that a mesoscale model, with a minimal number of parameters, can well describe the thermomechanical and mechanochemical behavior of homogeneous DNA at thermal equilibrium under tension and torque. We predict critical temperatures for denaturation under torque and stretch, phase diagrams for stable DNA, probe/response profiles under mechanical loads, and the density of dsDNA as a function of stretch and twist. We compare our predictions with available single molecule manipulation experiments and find strong agreement. In particular we elucidate the difference between angularly constrained and unconstrained overstretching. We propose that the smoothness of the angularly constrained overstretching transition is a consequence of the molecule being in the vicinity of criticality for a broad range of values of applied tension.

Description: Features of path dependent energy transfer in a dual-ring light-harvesting (LH2) complexes (B850) system have been examined in detail systematically. The Frenkel-Dirac time dependent variational method with the Davydov D 1 Ansatz is employed with detailed evolution of polaron dynamics in real space readily obtained. It is found that the phase of the transmission amplitude through the LH2 complexes plays an important role in constructing the coherent excitonic energy transfer. It is also found that the symmetry breaking caused by the dimerization of bacteriochlorophylls and coherence or correlation between two rings will be conducive in enhancing the exciton transfer efficiency.

Description: Electrostatic forces enormously impact the structure, interactions, and function of biomolecules. We perform all-atom molecular dynamics simulations for 5 proteins and 5 RNAs to determine the dependence on ionic strength of the ion and water charge distributions surrounding the biomolecules, as well as the contributions of ions to the electrostatic free energy of interaction between the biomolecule and the surrounding salt solution (for a total of 40 different biomolecule/solvent combinations). Although water provides the dominant contribution to the charge density distribution and to the electrostatic potential even in 1M NaCl solutions, the contributions of water molecules and of ions to the total electrostatic interaction free energy with the solvated biomolecule are comparable. The electrostatic biomolecule/solvent interaction energies and the total charge distribution exhibit a remarkable insensitivity to salt concentrations over a huge range of salt concentrations (20 mM to 1M NaCl). The electrostatic potentials near the biomolecule's surface obtained from the MD simulations differ markedly, as expected, from the potentials predicted by continuum dielectric models, even though the total electrostatic interaction free energies are within 11% of each other.

Description: We developed a statistical thermodynamic algorithm for analyzing solvent-induced folding/unfolding transitions of proteins. The energetics of protein transitions is governed by the interplay between the cavity formation contribution and the term reflecting direct solute-cosolvent interactions. The latter is viewed as an exchange reaction in which the binding of a cosolvent to a solute is accompanied by release of waters of hydration to the bulk. Our model clearly differentiates between the stoichiometric and non-stoichiometric interactions of solvent or co-solvent molecules with a solute. We analyzed the urea- and glycine betaine (GB)-induced conformational transitions of model proteins of varying size which are geometrically approximated by a sphere in their native state and a spherocylinder in their unfolded state. The free energy of cavity formation and its changes accompanying protein transitions were computed based on the concepts of scaled particle theory. The free energy of direct solute-cosolvent interactions were analyzed using empirical parameters previously determined for urea and GB interactions with low molecular weight model compounds. Our computations correctly capture the mode of action of urea and GB and yield realistic numbers for (∂ΔG°/∂a 3 ) T,P which are related to the m-values of protein denaturation. Urea is characterized by negative values of (∂ΔG°/∂a 3 ) T,P within the entire range of urea concentrations analyzed. At concentrations below ∼1 M, GB exhibits positive values of (∂ΔG°/∂a 3 ) T,P which turn positive at higher GB concentrations. The balance between the thermodynamic contributions of cavity formation and direct solute-cosolvent interactions that, ultimately, defines the mode of cosolvent action is extremely subtle. A 20% increase or decrease in the equilibrium constant for solute-cosolvent binding may change the sign of (∂ΔG°/∂a 3 ) T,P thereby altering the mode of cosolvent action (stabilizing to destabilizing or vice versa ).

Description: We propose a new exact stochastic rejection-based simulation algorithm for biochemical reactions and extend it to systems with delays. Our algorithm accelerates the simulation by pre-computing reaction propensity bounds to select the next reaction to perform. Exploiting such bounds, we are able to avoid recomputing propensities every time a (delayed) reaction is initiated or finished, as is typically necessary in standard approaches. Propensity updates in our approach are still performed, but only infrequently and limited for a small number of reactions, saving computation time and without sacrificing exactness. We evaluate the performance improvement of our algorithm by experimenting with concrete biological models.

Description: We study the mechanical unfolding of a simple model protein. The Langevin dynamics results are analyzed using Markov-model methods which allow to describe completely the configurational space of the system. Using transition-path theory we also provide a quantitative description of the unfolding pathways followed by the system. Our study shows a complex dynamical scenario. In particular, we see that the usual one-dimensional picture: free-energy vs end-to-end distance representation, gives a misleading description of the process. Unfolding can occur following different pathways and configurations which seem to play a central role in one-dimensional pictures are not the intermediate states of the unfolding dynamics.

Description: In recent years, much effort has focused on the early stages of aggregation and the formation of amyloid oligomers. Aggregation processes for these proteins are complex and their non-equilibrium nature makes any experimental study very difficult. Under these conditions, simulations provide a useful alternative for understanding the dynamics of the early stages of oligomerization. Here, we focus on the non-Aβ amyloid component (NAC) of the monomer, dimer, and trimer of α-synuclein, an important 35-residue sequence involved in the aggregation and fibrillation of this protein associated with Parkinson's disease. Using Hamiltonian and temperature replica exchange molecular dynamics simulations combined with the coarse grained Optimized Potential for Efficient peptide structure Prediction potential, we identify the role of the various regions and the secondary structures for the onset of oligomerization. For this sequence, we clearly observe the passage from α-helix to β-sheet, a characteristic transition of amyloid proteins. More precisely, we find that the NAC monomer is highly structured with two α-helical regions, between residues 2-13 and 19-25. As the dimer and trimer form, β-sheet structures between residues 2-14 and 26-34 appear and rapidly structure the system. The resulting conformations are much more structured than similar dimers and trimers of β-amyloid and amylin proteins and yet display a strong polymorphism at these early stages of aggregation. In addition to its inherent experimental interest, comparison with other sequences shows that NAC could be a very useful numerical model for understanding the onset of aggregation.

Description: The phase behaviors and membrane properties of small unilamellar vesicles have been explored at different temperatures by dissipative particle dynamics simulations. The vesicles spontaneously formed by model lipids exhibit pre-transition from gel to ripple phase and main transition from ripple to liquid phase. The vesicle shape exhibits the faceted feature at low temperature, becomes more sphere-like with increasing temperature, but loses its sphericity at high temperature. As the temperature rises, the vesicle size grows but the membrane thickness declines. The main transition (T m ) can be identified by the inflection point. The membrane structural characteristics are analyzed. The inner and outer leaflets are asymmetric. The length of the lipid tail and area density of the lipid head in both leaflets decrease with increasing temperature. However, the mean lipid volume grows at low temperature but declines at high temperature. The membrane mechanical properties are also investigated. The water permeability grows exponentially with increasing T but the membrane tension peaks at T m . Both the bending and stretching moduli have their minima near T m . Those results are consistent with the experimental observations, indicating that the main signatures associated with phase transition are clearly observed in small unilamellar vesicles.

Description: We developed a model describing the structure and contractile mechanism of the actomyosin ring in fission yeast, Schizosaccharomyces pombe . The proposed ring includes actin, myosin, and α-actinin, and is organized into a structure similar to that of muscle sarcomeres. This structure justifies the use of the sliding-filament mechanism developed by Huxley and Hill, but it is probably less organized relative to that of muscle sarcomeres. Ring contraction tension was generated via the same fundamental mechanism used to generate muscle tension, but some physicochemical parameters were adjusted to be consistent with the proposed ring structure. Simulations allowed an estimate of ring constriction tension that reproduced the observed ring constriction velocity using a physiologically possible, self-consistent set of parameters. Proposed molecular-level properties responsible for the thousand-fold slower constriction velocity of the ring relative to that of muscle sarcomeres include fewer myosin molecules involved, a less organized contractile configuration, a low α-actinin concentration, and a high resistance membrane tension. Ring constriction velocity is demonstrated as an exponential function of time despite a near linear appearance. We proposed a hypothesis to explain why excess myosin heads inhibit constriction velocity rather than enhance it. The model revealed how myosin concentration and elastic resistance tension are balanced during cytokinesis in S. pombe .

Description: The structural stability and function of biomolecules is strongly influenced by the dynamics and hydrogen bonding of interfacial water. Understanding and characterizing the dynamics of these water molecules require a surface-sensitive technique such as two-dimensional vibrational sum-frequency generation (2DSFG) spectroscopy. We have combined theoretical 2DSFG calculations with molecular dynamics simulations in order to investigate the dynamics of water near different lipid and surfactant monolayer surfaces. We show that 2DSFG can distinguish the dynamics of interfacial water as a function of the lipid charge and headgroup chemistry. The dynamics of water is slow compared to the bulk near water-zwitterionic and water-anionic interfaces due to conformational constraints on interfacial water imposed by strong phosphate-water hydrogen bonding. The dynamics of water is somewhat faster near water-cationic lipid interfaces as no such constraint is present. Using hydrogen bonding and rotational correlation functions, we characterize the dynamics of water as a function of the distance from the interface between water and zwitterionic lipids. We find that there is a transition from bulk-like to interface-like dynamics approximately 7 Å away from a zwitterionic phosphatidylcholine monolayer surface.

Description: The Histone-like Nucleoid Structuring protein (H-NS) is a nucleoid-associated protein, which is involved in both gene regulation and DNA compaction. Although it is a key player in genome organization by forming bridges between DNA duplexes, the precise structure of complexes of DNA and H-NS proteins is still not well understood. In particular, it is not clear whether the structure of DNA/H-NS complexes in the living cell is similar to that of complexes deposited on mica surfaces, which may be observed by AFM microscopy. A coarse-grained model, which helps getting more insight into this question, is described and analyzed in the present paper. This model is able of describing both the bridging of bacterial DNA by H-NS in the bulk and the deposition and equilibration of the complex on a charged surface. Simulations performed with the model reveal that a slight attraction between DNA and the charged surface is sufficient to let DNA/H-NS complexes reorganize from 3D coils to planar plasmids bridged by H-NS proteins similar to those observed by AFM microscopy. They furthermore highlight the antagonistic effects of the interactions between DNA and the surface. Indeed, increasing these interactions slows down the equilibration of naked plasmids on the surface but, on the other hand, enables a faster equilibration of DNA/H-NS complexes. Based on the distribution of the lifetimes of H-NS bridges and the time evolution of the number of trans -binding protein dimers during equilibration of the complexes on the surface, it is argued that the decrease of the equilibration time of the complex upon increase of the interaction strength between DNA and the surface is ascribable to the associated decrease of the probability to form new bridges between DNA and the proteins.

Description: The influence of high hydrostatic pressure on the structure and protein-protein interaction potential of highly concentrated lysozyme solutions up to about 370 mg ml −1 was studied and analyzed using small-angle X-ray scattering in combination with a liquid-state theoretical approach. In the concentration region below 200 mg ml −1 , the interaction parameters of lysozyme solutions are affected by pressure in a nonlinear way, which is probably due to significant changes in the structural properties of bulk water, i.e., due to a solvent-mediated effect. Conversely, for higher concentrated protein solutions, where hydration layers below ∼4 water molecules are reached, the interaction potential turns rather insensitive to compression. The onset of transient (dynamic) clustering is envisaged in this concentration range. Our results also show that pressure suppresses protein nucleation, aggregation and finally crystallization in supersaturated condensed protein solutions. These findings are of importance for controlling and fine-tuning protein crystallization. Moreover, these results are also important for understanding the high stability of highly concentrated protein solutions (as they occur intracellularly) in organisms thriving under hydrostatic pressure conditions such as in the deep sea, where pressures up to the kbar-level are reached.

Description: Hybrid schemes combining the strength of molecular dynamics (MD) and Metropolis Monte Carlo (MC) offer a promising avenue to improve the sampling efficiency of computer simulations of complex systems. A number of recently proposed hybrid methods consider new configurations generated by driving the system via a non-equilibrium MD (neMD) trajectory, which are subsequently treated as putative candidates for Metropolis MC acceptance or rejection. To obey microscopic detailed balance, it is necessary to alter the momentum of the system at the beginning and/or the end of the neMD trajectory. This strict rule then guarantees that the random walk in configurational space generated by such hybrid neMD-MC algorithm will yield the proper equilibrium Boltzmann distribution. While a number of different constructs are possible, the most commonly used prescription has been to simply reverse the momenta of all the particles at the end of the neMD trajectory (“one-end momentum reversal”). Surprisingly, it is shown here that the choice of momentum reversal prescription can have a considerable effect on the rate of convergence of the hybrid neMD-MC algorithm, with the simple one-end momentum reversal encountering particularly acute problems. In these neMD-MC simulations, different regions of configurational space end up being essentially isolated from one another due to a very small transition rate between regions. In the worst-case scenario, it is almost as if the configurational space does not constitute a single communicating class that can be sampled efficiently by the algorithm, and extremely long neMD-MC simulations are needed to obtain proper equilibrium probability distributions. To address this issue, a novel momentum reversal prescription, symmetrized with respect to both the beginning and the end of the neMD trajectory (“symmetric two-ends momentum reversal”), is introduced. Illustrative simulations demonstrate that the hybrid neMD-MC algorithm robustly yields a correct equilibrium probability distribution with this prescription.

Description: Water plays an essential role in the structure and function of proteins, particularly in the less understood class of membrane proteins. As the first of its kind, channelrhodopsin is a light-gated cation channel and paved the way for the new and vibrant field of optogenetics, where nerve cells are activated by light. Still, the molecular mechanism of channelrhodopsin is not understood. Here, we applied time-resolved FT-IR difference spectroscopy to channelrhodopsin-1 from Chlamydomonas augustae. It is shown that the (conductive) P 2 380 intermediate decays with τ ≈ 40 ms and 200 ms after pulsed excitation. The vibrational changes between the closed and the conductive states were analyzed in the X-H stretching region (X = O, S, N), comprising vibrational changes of water molecules, sulfhydryl groups of cysteine side chains and changes of the amide A of the protein backbone. The O-H stretching vibrations of “dangling” water molecules were detected in two different states of the protein using H 2 18 O exchange. Uncoupling experiments with a 1:1 mixture of H 2 O:D 2 O provided the natural uncoupled frequencies of the four O-H (and O-D) stretches of these water molecules, each with a very weakly hydrogen-bonded O-H group (3639 and 3628 cm −1 ) and with the other O-H group medium (3440 cm −1 ) to moderately strongly (3300 cm −1 ) hydrogen-bonded. Changes in amide A and thiol vibrations report on global and local changes, respectively, associated with the formation of the conductive state. Future studies will aim at assigning the respective cysteine group(s) and at localizing the “dangling” water molecules within the protein, providing a better understanding of their functional relevance in Ca ChR1.

Description: Atomistic molecular dynamics simulation of an aqueous solution of the small protein HP-36 has been carried out with explicit solvent at room temperature. Efforts have been made to explore the influence of the protein on the relative packing and ordering of water molecules around its secondary structures, namely, three α-helices. The calculations reveal that the inhomogeneous water ordering and density distributions around the helices are correlated with their relative hydrophobicity. Importantly, we have identified the existence of a narrow relatively dehydrated region containing randomly organized “quasi-free” water molecules beyond the first layer of “bound” waters at the protein surface. These water molecules with relatively weaker binding energies form the transition state separating the “bound” and “free” water molecules at the interface. Further, increased contribution of solid-like caging motions of water molecules around the protein is found to be responsible for reduced fluidity of the hydration layer. Interestingly, we notice that the hydration layer of helix-3 is more fluidic with relatively higher entropy as compared to the hydration layers of the other two helical segments. Such characteristics of helix-3 hydration layer correlate well with the activity of HP-36, as helix-3 contains the active site of the protein.

Description: Small open chemical systems, typically associated with far-from-equilibrium, nonlinear stochastic dynamics, offer the appropriate framework to elucidate biological phenomena at the cellular scale. Stochastic differential equations of Langevin-type are employed to establish the relation between the departure from equilibrium and the time cross-correlation functions of concentration fluctuations for chemical species susceptible to oscillate. Except in the immediate vicinity of the Hopf bifurcation, the results are in agreement with simulations of the chemical master equation but always differ from the prediction obtained for linear deterministic dynamics. In general, the magnitude of the asymmetry of time correlation functions definitely depends on the reaction flux circulating in an open system but also on the details of the nonlinearities of deterministic dynamics.

Description: The long four-helix bundle antifreeze protein Maxi contains an unusual core for a globular protein. More than 400 ordered waters between the helices form a nano-pore of internal water about 150 Å long. Molecular dynamics simulations of hydrated Maxi were carried out using the CHARMM27 protein forcefield and the TIP3P water model. Solvation in the core and non-core first hydration shell was analyzed in terms of water-water H-bond distance-angle distributions. The core had an increased population of low-angle H-bonds between water pairs relative to bulk water. Enhancement of low angle H-bonds was particularly pronounced for water pairs at the interfaces between apolar and polar regions inside the protein core, characteristic of the anchored clathrate solvation structure seen previously in the ice-nuclei binding surfaces of type I, type III, and beta-helical antifreeze proteins. Anchored clathrate type solvation structure was not seen in the exterior solvation shell except around residues implicated in ice binding. Analysis of solvation dynamics using water residence times and diffusion constants showed that exterior solvation shell waters exchanged rapidly with bulk water, with no difference between ice-binding and non-binding residues. Core waters had about ten-fold slower diffusion than bulk water. Water residence times around core residues averaged about 8 ps, similar to those on the exterior surface, but they tended to exchange primarily with other core water, resulting in longer, 〉40 ps residence times within the core. Preferential exchange or diffusion of the water along the long axis of the water core of Maxi was not detected.

Description: We study the mechanical unfolding of a simple model protein. The Langevin dynamics results are analyzed using Markov-model methods which allow to describe completely the configurational space of the system. Using transition-path theory we also provide a quantitative description of the unfolding pathways followed by the system. Our study shows a complex dynamical scenario. In particular, we see that the usual one-dimensional picture: free-energy vs end-to-end distance representation, gives a misleading description of the process. Unfolding can occur following different pathways and configurations which seem to play a central role in one-dimensional pictures are not the intermediate states of the unfolding dynamics.

Description: We present experimental results on photofragmentation of cooled fragments issued from the photofragmentation of cold parent ions. The cooling of the daughter ions at a few K allows its characterization not only through its fragmentation pattern but also through its well resolved electronic spectroscopy. The proof of principle of the method is demonstrated on the photofragment resulting from C α –C β bond rupture in protonated tyrosine (TyrH + ). The analysis of the daughter ion (m/z 108) photofragmentation spectrum is in agreement with the proposed mechanism implying a proton transfer to the phenyl ring as the first step of the fragmentation mechanism of TyrH + .

Description: The protein folding funnel paradigm suggests that folding and unfolding proceed as directed diffusion in a multidimensional free energy surface where a multitude of pathways can be traversed during the protein's sojourn from initial to final state. However, finding even a single pathway, with the detail chronicling of intermediates, is an arduous task. In this work we explore the free energy surface of unfolding pathway through umbrella sampling, for a small globular α-helical protein chicken-villin headpiece (HP-36) when the melting of secondary structures is induced by adding DMSO in aqueous solution. We find that the unfolding proceeds through the initial separation or melting of aggregated hydrophobic core that comprises of three phenylalanine residues (Phe7, Phe11, and Phe18). This separation is accompanied by simultaneous melting of the second helix. Unfolding is found to be a multistage process involving crossing of three consecutive minima and two barriers at the initial stage. At a molecular level, Phe18 is observed to reorient itself towards other hydrophobic grooves to stabilize the intermediate states. We identify the configuration of the intermediates and correlate the intermediates with those obtained in our previous works. We also give an estimate of the barriers for different transition states and observe the softening of the barriers with increasing DMSO concentration. We show that higher concentration of DMSO tunes the unfolding pathway by destabilizing the third minimum and stabilizing the second one, indicating the development of a solvent modified, less rugged pathway. The prime outcome of this work is the demonstration that mixed solvents can profoundly transform the nature of the energy landscape and induce unfolding via a modified route. A successful application of Kramer's rate equation correlating the free energy simulation results shows faster rate of unfolding with increasing DMSO concentration. This work perhaps presents the first systematic theoretical study of the effect of a chemical denaturant on the microscopic free energy surface and rates of unfolding of HP-36.

Description: In this study, we analyze correlations of vibrational motion on the surface of a small globular protein and in its hydration shell. In contrast to single particle hydration water dynamics, which are perturbed by interactions with the protein solute only in the first few hydration layers, we find that correlated, collective motions extend into the surrounding solvent on a 10 Å length scale, specifically at far-infrared frequencies below 100 cm −1 . As a function of frequency, we analyze the distribution of correlated longitudinal motions in the three-dimensional environment of the protein solute, as well as in the vicinity of different protein-water interfaces. An anisotropic distribution of these correlations is observed, which is related to specific protein-water vibrations and interactions at the interfaces, as well as flexibilities of solvent exposed sites. Our results show that coupling of protein and water dynamics leaves a three-dimensional imprint in the collective dynamics of its hydration shell, and we discuss potential implications for biomolecular function, e.g., molecular recognition and binding, and the dynamical coupling of proteins to their native solvation environment.

Description: A new method is introduced to compute X-ray solution scattering profiles from atomic models of macromolecules. The three-dimensional version of the Reference Interaction Site Model (RISM) from liquid-state statistical mechanics is employed to compute the solvent distribution around the solute, including both water and ions. X-ray scattering profiles are computed from this distribution together with the solute geometry. We describe an efficient procedure for performing this calculation employing a Lebedev grid for the angular averaging. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulations up to wide angle for two proteins (lysozyme and myoglobin) in water, as well as the small-angle profiles for a dozen biomolecules taken from the BioIsis.net database. The RISM model is especially well-suited for studies of nucleic acids in salt solution. Use of fiber-diffraction models for the structure of duplex DNA in solution yields close agreement with the observed scattering profiles in both the small and wide angle scattering (SAXS and WAXS) regimes. In addition, computed profiles of anomalous SAXS signals (for Rb + and Sr 2+ ) emphasize the ionic contribution to scattering and are in reasonable agreement with experiment. In cases where an absolute calibration of the experimental data at q = 0 is available, one can extract a count of the excess number of waters and ions; computed values depend on the closure that is assumed in the solution of the Ornstein–Zernike equations, with results from the Kovalenko–Hirata closure being closest to experiment for the cases studied here.

Description: We present a simulation scheme to calculate defect formation free energies at a molecular crystal/water interface based on force-field molecular dynamics simulations. To this end, we adopt and modify existing approaches to calculate binding free energies of biological ligand/receptor complexes to be applicable to common surface defects, such as step edges and kink sites. We obtain statistically accurate and reliable free energy values for the aspirin/water interface, which can be applied to estimate the distribution of defects using well-established thermodynamic relations. As a show case we calculate the free energy upon dissolving molecules from kink sites at the interface. This free energy can be related to the solubility concentration and we obtain solubility values in excellent agreement with experimental results.

Description: Rugged energy landscapes find wide applications in diverse fields ranging from astrophysics to protein folding. We study the dependence of diffusion coefficient ( D ) of a Brownian particle on the distribution width (ɛ) of randomness in a Gaussian random landscape by simulations and theoretical analysis. We first show that the elegant expression of Zwanzig [Proc. Natl. Acad. Sci. U.S.A.85, 2029 (1988)] for D (ɛ) can be reproduced exactly by using the Rosenfeld diffusion-entropy scaling relation. Our simulations show that Zwanzig's expression overestimates D in an uncorrelated Gaussian random lattice – differing by almost an order of magnitude at moderately high ruggedness. The disparity originates from the presence of “three-site traps” (TST) on the landscape – which are formed by the presence of deep minima flanked by high barriers on either side. Using mean first passage time formalism, we derive a general expression for the effective diffusion coefficient in the presence of TST, that quantitatively reproduces the simulation results and which reduces to Zwanzig's form only in the limit of infinite spatial correlation. We construct a continuous Gaussian field with inherent correlation to establish the effect of spatial correlation on random walk. The presence of TSTs at large ruggedness (ɛ ≫ k B T ) gives rise to an apparent breakdown of ergodicity of the type often encountered in glassy liquids.

Description: While the theoretical description of population transfer subsequent to electronic excitation in combination with a line shape function description of vibrational dynamics in the context of 2D-spectroscopy is well-developed under the assumption of different timescales of population transfer and fluctuation dynamics, the treatment of the interplay between both kinds of processes lacks a comprehensive description. To bridge this gap, we use the cumulant expansion approach to derive response functions, which account for fluctuation dynamics and population transfer simultaneously. We compare 2D-spectra of a model system under different assumptions about correlations between fluctuations and point out under which conditions a simplified treatment is justified. Our study shows that population transfer and dissipative fluctuation dynamics cannot be described independent of each other in general. Advantages and limitations of the proposed calculation method and its compatibility with the modified Redfield description are discussed.

Description: We present evidence that following near-UV excitation, protonated tyrosine- or phenylalanine–containing peptides undergo intersystem crossing to produce a triplet species. This pathway competes with direct dissociation from the excited electronic state and with dissociation from the electronic ground state subsequent to internal conversion. We employ UV-IR double-resonance photofragment spectroscopy to record conformer-specific vibrational spectra of cold peptides pre-excited to their S 1 electronic state. The absorption of tunable IR light by these electronically excited peptides leads to a drastic increase in fragmentation, selectively enhancing the loss of neutral phenylalanine or tyrosine side-chain, which are not the lowest dissociation channels in the ground electronic state. The recorded IR spectra evolve upon increasing the time delay between the UV and IR pulses, reflecting the dynamics of the intersystem crossing on a timescale of ∼80 ns and

Description: Small viruses that belong, for example, to the Picornaviridae , such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 10 6 all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200 000) can leave the capsid and be replaced by water molecules from the outside in about 25 μs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.

Description: Time-dependent fluorescence shift (TDFS) of Laurdan embedded in phospholipid bilayers reports on hydration and mobility of the phospholipid acylgroups. Exchange of H 2 O with D 2 O prolongs the lifetime of lipid-water and lipid-water-lipid interactions, which is reflected in a significantly slower TDFS kinetics. Combining TDFS measurements in H 2 O and D 2 O hydrated bilayers with atomistic molecular dynamics (MD) simulations provides a unique tool for characterization of the hydrogen bonding at the acylgroup level of lipid bilayers. In this work, we use this approach to study the influence of fluoride anions on the properties of cationic bilayers composed of trimethylammonium-propane (DOTAP). The results obtained for DOTAP are confronted with those for neutral phosphatidylcholine (DOPC) bilayers. Both in DOTAP and DOPC H 2 O/D 2 O exchange prolongs hydrogen-bonding lifetime and does not disturb bilayer structure. These results are confirmed by MD simulations. TDFS experiments show, however, that for DOTAP this effect is cancelled in the presence of fluoride ions. We interpret these results as evidence that strongly hydrated fluoride is able to steal water molecules that bridge lipid carbonyls. Consequently, when attracted to DOTAP bilayer, fluoride disrupts the local hydrogen-bonding network, and the differences in TDFS kinetics between H 2 O and D 2 O hydrated bilayers are no longer observed. A distinct behavior of fluoride is also evidenced by MD simulations, which show different lipid-ion binding for Cl − and F − .

Description: The interaction of DNA with proteins occurs over a wide range of length scales, and depends critically on its local structure. In particular, recent experimental work suggests that the intrinsic curvature of DNA plays a significant role on its protein-binding properties. In this work, we present a coarse grained model of DNA that is capable of describing base-pairing, hybridization, major and minor groove widths, and local curvature. The model represents an extension of the recently proposed 3SPN.2 description of DNA [D. M. Hinckley, G. S. Freeman, J. K. Whitmer, and J. J. de Pablo, J. Chem. Phys.139, 144903 (2013)], into which sequence-dependent shape and mechanical properties are incorporated. The proposed model is validated against experimental data including melting temperatures, local flexibilities, dsDNA persistence lengths, and minor groove width profiles.

Description: GALA is a 30 amino acid synthetic peptide consisting of a Glu-Ala-Leu-Ala repeat and is known to undergo a reversible structural transition from a disordered to an α-helical structure when changing the pH from basic to acidic values. In its helical state GALA can insert into and disintegrate lipid membranes. This effect has generated much interest in GALA as a candidate for pH triggered, targeted drug delivery. GALA also serves as a well-defined model system to understand cell penetration mechanisms and protein folding triggered by external stimuli. Structural transitions of GALA in solution have been studied extensively. However, cell penetration is an interfacial effect and potential biomedical applications of GALA would involve a variety of surfaces, e.g., nanoparticles, lipid membranes, tubing, and liquid-gas interfaces. Despite the apparent importance of interfaces in the functioning of GALA, the effect of surfaces on the reversible folding of GALA has not yet been studied. Here, we use sum frequency generation vibrational spectroscopy (SFG) to probe the structural response of GALA at the air-water interface and IR spectroscopy to follow GALA folding in bulk solution. We combine the SFG data with molecular dynamics simulations to obtain a molecular-level picture of the interaction of GALA with the air-water interface. Surprisingly, while the fully reversible structural transition was observed in solution, at the water-air interface, a large fraction of the GALA population remained helical at high pH. This “stickiness” of the air-water interface can be explained by the stabilizing interactions of hydrophobic leucine and alanine side chains with the water surface.

Description: The “dynamic” or “glass” transition in biomolecules is as important to their functioning as the folding process. This transition occurs in the low temperature regime and has been related to the onset of biochemical activity that is dependent on the hydration level. This protein transition is believed to be triggered by the strong hydrogen bond coupling in the hydration water. We study the vibrational bending mode and measure it using Fourier Transform Infrared spectroscopy. We demonstrate that at the molecular level the hydration water bending mode bonds the C=O and N–H peptide groups, and find that the temperature of the “dynamic” protein transition is the same as the fragile-to-strong dynamic transition in confined water. The fragile-to-strong dynamic transition in water governs the nature of the H bonds between water and peptides and appears to be universal in supercooled glass-forming liquids.

Description: Structural bioinformatics and van der Waals density functional theory are combined to investigate the mechanochemical impact of a major class of histone-DNA interactions, namely, the formation of salt bridges between arginine residues in histones and phosphate groups on the DNA backbone. Principal component analysis reveals that the configurational fluctuations of the sugar-phosphate backbone display sequence-specific directionality and variability, and clustering of nucleosome crystal structures identifies two major salt-bridge configurations: a monodentate form in which the arginine end-group guanidinium only forms one hydrogen bond with the phosphate, and a bidentate form in which it forms two. Density functional theory calculations highlight that the combination of sequence, denticity, and salt-bridge positioning enables the histones to apply a tunable mechanochemical stress to the DNA via precise and specific activation of backbone deformations. The results suggest that selection for specific placements of van der Waals contacts, with high-precision control of the spatial distribution of intermolecular forces, may serve as an underlying evolutionary design principle for the structure and function of nucleosomes, a conjecture that is corroborated by previous experimental studies.

Description: Matrix-assisted laser desorption ionization (MALDI) has been widely used in the mass analysis of biomolecules; however, there are a lot of debates about the ionization mechanisms. Previous studies have indicated that S 1 -S 1 annihilation might be a key process in the generation of primary ions. This study investigates S 1 -S 1 annihilation by examining the time-resolved fluorescence spectra of 12 matrices. No S 1 -S 1 annihilation was observed in six of these matrices (3-hydroxy-picolinic acid, 6-aza-2-thiothymine, 2,4-dihydroxy-acetophenone, 2,6-dihydroxy-acetophenone, 2,4,6-trihydroxy-acetophenone, and ferulic acid). We observed two matrix molecules reacting in an electronically excited state (S 1 ) in five of these matrices (2,5-dihydroxybenzoic acid, α-cyano-4-hydroxycinnamic acid, 2,5-dihydroxy-acetophenone, 2,3-dihydroxybenzoic acid, and 2,6-dihydroxybenzoic acid), and S 1 -S 1 annihilation was a possible reaction. Among these five matrices, no S 1 -S 1 annihilation was observed for 2,3-dihydroxybenzoic acid in typical peak power region of nanosecond laser pulses in MALDI, but a very small value of reaction rate constant was observed only in the high peak power region. The excited-state lifetime of sinapinic acid was too short to determine whether the molecules reacted in an electronically excited state. No correlation was observed between the ion generation efficiency of MALDI and S 1 -S 1 annihilation. The results indicate that the proposal of S 1 -S 1 annihilation is unnecessary in MALDI and energy pooling model for MALDI ionization mechanism has to be modified.

Description: We present a polarizable water model for the Dissipative Particle Dynamics (DPD) method. Employing long-range electrostatics and Drude oscillators, we calibrate the model using the compressibility and the dielectric constant of water. We validate the model by sampling the dielectric properties of solutions of sodium chloride at various concentrations. Additionally, we apply our model in equilibrium and electroporation simulations of a pure dipalmitoylphosphatidylcholine (DPPC) bilayer, a pure cholesterol domain and a mixed DPPC-cholesterol membrane in polarizable water. Finally, we simulate the transport of a short DNA segment through a DPPC bilayer driven by an external electric field. The new water model is suitable for the DPD simulations of systems where polarization effects play an essential role.

Description: DNA amplification is the process of replication of a specified DNA sequence in vitro through time-dependent manipulation of its external environment. A theoretical framework for determination of the optimal dynamic operating conditions of DNA amplification reactions, for any specified amplification objective, is presented based on first-principles biophysical modeling and control theory. Amplification of DNA is formulated as a problem in control theory with optimal solutions that can differ considerably from strategies typically used in practice. Using the Polymerase Chain Reaction as an example, sequence-dependent biophysical models for DNA amplification are cast as control systems, wherein the dynamics of the reaction are controlled by a manipulated input variable. Using these control systems, we demonstrate that there exists an optimal temperature cycling strategy for geometric amplification of any DNA sequence and formulate optimal control problems that can be used to derive the optimal temperature profile. Strategies for the optimal synthesis of the DNA amplification control trajectory are proposed. Analogous methods can be used to formulate control problems for more advanced amplification objectives corresponding to the design of new types of DNA amplification reactions.

Description: The treatment of bending and buckling of stiff biopolymer filaments by the popular worm-like chain model does not provide adequate understanding of these processes at the microscopic level. Thus, we have used the atomistic molecular-dynamic simulations and the Amber03 force field to examine the compression buckling of α-helix (AH) filaments at room temperature. It was found that the buckling instability occurs in AHs at the critical force f c in the range of tens of pN depending on the AH length. The decrease of the force f c with the contour length follows the prediction of the classic thin rod theory. At the force f c the helical filament undergoes the swift and irreversible transition from the smoothly bent structure to the buckled one. A sharp kink in the AH contour arises at the transition, accompanied by the disruption of the hydrogen bonds in its vicinity. The kink defect brings in an effective softening of the AH molecule at buckling. Nonbonded interactions between helical branches drive the rearrangement of a kinked AH into the ultimate buckled structure of a compact helical hairpin described earlier in the literature.

Description: We are interested in the free energies of transferring nonpolar solutes into aqueous NaCl solutions with salt concentrations upwards of 2 M, the Hofmeister regime. We use the semi-explicit assembly (SEA) computational model to represent these electrolyte solutions. We find good agreement with experiments (Setschenow coefficients) on 43 nonpolar and polar solutes and with TIP3P explicit-solvent simulations. Besides being much faster than explicit solvent calculations, SEA is more accurate than the PB models we tested, successfully capturing even subtle salt effects in both the polar and nonpolar components of solvation. We find that the salt effects are mainly due to changes in the cost of forming nonpolar cavities in aqueous NaCl solutions, and not mainly due to solute-ion electrostatic interactions.

Description: The thermodynamic properties of DNA circular molecules are investigated by a new path integral computational method which treats in the real space the fundamental forces stabilizing the molecule. The base pair and stacking contributions to the classical action are evaluated separately by simulating a broad ensemble of twisted conformations. We obtain, for two short sequences, a free energy landscape with multiple wells corresponding to the most convenient values of helical repeat. Our results point to a intrinsic flexibility of the circular structures in which the base pair fluctuations move the system from one well to the next thus causing the local unwinding of the helix. The latter is more pronounced in the shorter sequence whose cyclization causes a higher bending stress. The entropic reductions associated to the formation of the ordered helicoidal structure are estimated.

Description: Multi-scale aggregation to network formation of interacting proteins (H3.1) are examined by a knowledge-based coarse-grained Monte Carlo simulation as a function of temperature and the number of protein chains, i.e., the concentration of the protein. Self-assembly of corresponding homo-polymers of constitutive residues (Cys, Thr, and Glu) with extreme residue-residue interactions, i.e., attractive (Cys–Cys), neutral (Thr–Thr), and repulsive (Glu–Glu), are also studied for comparison with the native protein. Visual inspections show contrast and similarity in morphological evolutions of protein assembly, aggregation of small aggregates to a ramified network from low to high temperature with the aggregation of a Cys-polymer, and an entangled network of Glu and Thr polymers. Variations in mobility profiles of residues with the concentration of the protein suggest that the segmental characteristic of proteins is altered considerably by the self-assembly from that in its isolated state. The global motion of proteins and Cys polymer chains is enhanced by their interacting network at the low temperature where isolated chains remain quasi-static. Transition from globular to random coil transition, evidenced by the sharp variation in the radius of gyration, of an isolated protein is smeared due to self-assembly of interacting networks of many proteins. Scaling of the structure factor S ( q ) with the wave vector q provides estimates of effective dimension D of the mass distribution at multiple length scales in self-assembly. Crossover from solid aggregates ( D ∼ 3) at low temperature to a ramified fibrous network ( D ∼ 2) at high temperature is observed for the protein H3.1 and Cys polymers in contrast to little changes in mass distribution ( D ∼ 1.6) of fibrous Glu- and Thr-chain configurations.

Description: Features of path dependent energy transfer in a dual-ring light-harvesting (LH2) complexes (B850) system have been examined in detail systematically. The Frenkel-Dirac time dependent variational method with the Davydov D 1 Ansatz is employed with detailed evolution of polaron dynamics in real space readily obtained. It is found that the phase of the transmission amplitude through the LH2 complexes plays an important role in constructing the coherent excitonic energy transfer. It is also found that the symmetry breaking caused by the dimerization of bacteriochlorophylls and coherence or correlation between two rings will be conducive in enhancing the exciton transfer efficiency.

Description: A new method is introduced to compute X-ray solution scattering profiles from atomic models of macromolecules. The three-dimensional version of the Reference Interaction Site Model (RISM) from liquid-state statistical mechanics is employed to compute the solvent distribution around the solute, including both water and ions. X-ray scattering profiles are computed from this distribution together with the solute geometry. We describe an efficient procedure for performing this calculation employing a Lebedev grid for the angular averaging. The intensity profiles (which involve no adjustable parameters) match experiment and molecular dynamics simulations up to wide angle for two proteins (lysozyme and myoglobin) in water, as well as the small-angle profiles for a dozen biomolecules taken from the BioIsis.net database. The RISM model is especially well-suited for studies of nucleic acids in salt solution. Use of fiber-diffraction models for the structure of duplex DNA in solution yields close agreement with the observed scattering profiles in both the small and wide angle scattering (SAXS and WAXS) regimes. In addition, computed profiles of anomalous SAXS signals (for Rb + and Sr 2+ ) emphasize the ionic contribution to scattering and are in reasonable agreement with experiment. In cases where an absolute calibration of the experimental data at q = 0 is available, one can extract a count of the excess number of waters and ions; computed values depend on the closure that is assumed in the solution of the Ornstein–Zernike equations, with results from the Kovalenko–Hirata closure being closest to experiment for the cases studied here.

Description: Understanding and controlling the transportation of water molecules across carbon nanotube (CNT) is of great importance in bio-nanotechnology. In this paper, we systematically investigate the water transporting behaviors (i.e., water flow rate) inside the CNT in the presence of lipid membranes by using all atom molecular dynamic simulations. Our results show that the hydrophilicity of CNT as well as membrane thickness can have important impacts on the water flow rate. Interestingly, since the membrane thickness is temperature-dependent, the water flow rate can exhibit thermo-responsive behaviors. Further, we also provide insights into the effect of CNT on lipid membranes. It is found that all CNTs can increase the lipid tail order parameters and thicken the membrane at 320 K; while these effects are not obvious at 290 K. Importantly, we observe that the CNT with specific hydrophobicity has the least effect on membranes. The present study may give some useful advice on future experimental design of novel devices and sensors.

Description: The phase behaviors and membrane properties of small unilamellar vesicles have been explored at different temperatures by dissipative particle dynamics simulations. The vesicles spontaneously formed by model lipids exhibit pre-transition from gel to ripple phase and main transition from ripple to liquid phase. The vesicle shape exhibits the faceted feature at low temperature, becomes more sphere-like with increasing temperature, but loses its sphericity at high temperature. As the temperature rises, the vesicle size grows but the membrane thickness declines. The main transition (T m ) can be identified by the inflection point. The membrane structural characteristics are analyzed. The inner and outer leaflets are asymmetric. The length of the lipid tail and area density of the lipid head in both leaflets decrease with increasing temperature. However, the mean lipid volume grows at low temperature but declines at high temperature. The membrane mechanical properties are also investigated. The water permeability grows exponentially with increasing T but the membrane tension peaks at T m . Both the bending and stretching moduli have their minima near T m . Those results are consistent with the experimental observations, indicating that the main signatures associated with phase transition are clearly observed in small unilamellar vesicles.