ALBERT

Notes: The affinity of a ligand for a receptor is usually expressed in terms of the dissociation constant (Ki) of the drug-receptor complex, conveniently measured by the inhibition of radioligand binding. However, a ligand can be an antagonist, a partial agonist, or a full agonist, a property largely independent of its receptor affinity. This property can be quantitated as intrinsic activity (1A), which can range from 0 for a full antagonist to 1 for a full agonist. Although quantitative structure-activity relationship (QSAR) methods have been applied to the prediction of receptor affinity with considerable success, the prediction of IA, even qualitatively, has rarely been attempted. Because most traditional QSAR methods are limited to congeneric series, and there are often major structural differences between agonists and antagonists, this lack of success in predicting IA is understandable. To overcome this limitation, we used the method of comparative molecular field analysis (CoMFA), which, unlike traditional Hansch analysis, permits the inclusion of structurally dissimilar compounds in a single QSAR model. A structurally diverse set of 5-hydroxytryptamine1A (5-HT1A) receptor ligands, with literature IA data (determined by the inhibition of 5-HT sensitive forskolin-stimulated adenylate cyclase), was used to develop a 3-D QSAR model correlating intrinsic activity with molecular structure properties of 5HT1A receptor ligands. This CoMFA model had a crossvalidated r2 of 0.481, five components and final conventional r2 of 0.943. The receptor model suggests that agonist and antagonist ligands can share parts of a common binding site on the receptor, with a primary agonist binding region that is also occupied by antagonists and a secondary binding site accommodating the excess bulk present in the sidechains of many antagonists and partial agonists. The CoMFA steric field graph clearly shows that agonists tend to be “flatter” (more coplanar) than antagonists, consistent with the difference between the 5-HT1A agonist and antagonist pharmacophores proposed by Hibert and coworkers. The CoMFA electrostatic field graph suggests that, in the region surrounding the essential protonated aliphatic amino group, the positive molecular electrostatic potential may be weaker in antagonists as compared to agonists. Together, the steric and electrostatic maps suggest that in the secondary binding site region increased hydrophobic binding may enhance antagonist activity. These results demonstrate that CoMFA is capable of generating a statistically crossvalidated 3-D QSAR model that can successfully distinguish between agonist and antagonist 5-HT1A ligands. To the best of our knowledge, this is the first time this or any other QSAR method has been successfully applied to the correlation of structure with IA rather than potency or affinity. The analysis has suggested various structural features associated with agonist and antagonist behaviors of 5-HT1A ligands and thus should assist in the future design of drugs that act via 5-HT1A receptors. © 1993 John Wiley & Sons, Inc.

Notes: We consider the tree search problem for the recurrence relation that appears in the evaluation of molecular integrals over Cartesian Gaussian basis functions. A systematic way of performing tree search is shown. By applying the result of tree searching to the LRL2 method of Lindh, Ryu, and Liu (LRL) (J. Chem. Phys., 95, 5889 1991), which is an auxiliary function-based method, we obtain significant reductions of the floating point operations (FLOPS) counts in the K4 region. The resulting FLOPS counts in the K4 region are comparable up to [dd|dd] angular momentum cases to the LRL1 method of LRL, currently the method requiring least FLOPS for [dd|dd] and higher angular momentum basis functions. For [ff|ff], [gg|gg], [hh|hh], and [ii|ii] cases, the required FLOPS are 24, 40, 51, and 59%, respectively, less than the LRL1 method in the K4 region. These are the best FLOPS counts available in the literature for high angular momentum cases. Also, there will be no overhead in either the K2 or K0 region in implementing the present scheme. This should lead to more efficient codes of integral evaluations for higher angular momentum cases than any other existing codes. © 1993 John Wiley & Sons, Inc.

Notes: A method is proposed to perform computer simulations of protein dynamics in the long-time regime. The method is based upon a Monte Carlo technique. The only molecular degrees of freedom considered are bond rotations. All other degrees of freedom including the amide plane torsions are kept rigid. These constraints approximately account for all interactions related to chemical bonding. An individual Monte Carlo step adopts the Go and Scheraga algorithm where local conformational changes in a small window of the protein backbone are performed. By using correlated rotations, the conformation of residues outside the window remains invariant. To test the reliability of the method, the nonbonded interactions are turned off in the present application. Exact statistical averages are compared with values obtained from data of computer simulation involving 2 × 106 scans of the window along the protein backbone. Time is related to the number of scans of the window along the protein backbone. End-to-end distance autocorrelation functions decay to 1/e of its initial value in about 103-104 scans of the window algorithm. Time decay follows a stretched exponential Kohlrausch decay law. © 1993 John Wiley & Sons, Inc.

Notes: The antitumor drug cis-diamminedichloroplatinum(II) (cisplatin) binds preferentially to GpG and ApG sequences of DNA, forming N7,N7 intrastrand chelates. Molecular modeling of the intrastrand adducts have been handicapped, so far, by the lack of force-field data describing the Pt-guanine and Pt-adenine binding. We used ab initio calculations with relativistic pseudopotentials to evaluate three important parameters for the platinum-adenine model complex [Pt(NH3)3(Ade)]2+: (1) the force constant for the Pt—N7 bond bending out of the adenine plane; (2) the energy profile for the torsion about Pt—N7; (3) a set of fractional atomic charges that reproduce the ab initio potential for a number of space points placed around the adduct. A population analysis and comparative study on the tetrammine complex [Pt(NH3)4]2+ have shown that for platinum adenine is a better σ-donor than NH3, but its capacity as a π-acceptor is weak. © 1993 John Wiley & Sons, Inc.

Notes: A procedure is reported for the prediction of dense crystal structures of C-, H-, N-, O-, and F-containing organic compounds in the primitive triclinic, monoclinic, and orthorhombic space groups with Z ≤ 4. The crystal environments of molecules in 242 crystal structures have been analyzed to determine the common coordination sphere pattens. This led to the development of the MOLPAK (MOLecular PAcKing) program, which uses a rigid-body molecular structure probe to build packing arrangements (possible crystal structures) in the various space groups. A MOLPAK search, which involves the investigation of all unique orientations of a central molecule and the construction of the appropriate coordination patterns about the central molecule, provides a 3-D map of minimum unit cell volume as a function of the orientation of the central molecule. MOLPAK uses a repulsion-only potential and a preset threshold to place molecules in contact with each other. The 5-10 smallest volume packing arrangements from a search are subjected to a lattice energy minimization refinement with the WMIN program to yield possible crystal structures. The results are described from the analyses of several known compounds starting with the crystal molecular structures as the MOLPAK search probes in the P1, P21, P21/c, and P212121 space groups. In addition, several examples are given in which the search probes were created by AM1 geometry optimization of preliminary molecular models. More extensive data are given in supplementary tables. © 1993 John Wiley & Sons, Inc.

Notes: A fully functional parallel version of the molecular dynamics (MD) module of AMBER3a has been implemented. Procedures parallelized include the calculation of the long-range nonbonded Coulomb and Lennard-Jones interactions, generation of the pairlist, intramolecular bond, angle, dihedral, 1-4 nonbonded interaction terms, coordinate restraints, and the SHAKE bond constraint algorithm. As far as we can determine, this is the first published description where a distributed-memory MIMD parallel implementation of the SHAKE algorithm has been designed to treat not only hydrogen-containing bonds but also all heavy-atom bonds, and where “shaken” crosslinks are supported as well. We discuss the subtasking and partitioning of an MD time-step, load balancing the nonbonded evaluations, describe in algorithmic detail how parallelization of SHAKE was accomplished, and present speedup, efficiency, and benchmarking results achieved when this hypercube adaptation of the MD module AMBER was applied to several variant molecular systems. Results are presented for speedup and efficiency obtained on the nCUBE machine, using up to 128 processors, as well as benchmarks for performance comparisons with the CRAY YMP and FPS522 vector machines. © 1993 John Wiley & Sons, Inc.

Notes: We report the development of a new approximate method of calculating molecular surface areas. Our technique is based upon the method of Sharake and Rupley but incorporates several major advances. First, we represent the state of surface points as bits in a bit string so we can utilize Boolean operations to simultaneously turn off multiple test points in one Boolean AND operation. Second, we use a series of Boolean mask look-up tables to reduce the time complexity of the calculation of molecular surface area down to the same magnitude as doing a potential energy evaluation. When we use a 256 surface point sphere for all of the atoms in BPTI, a 454 nonhydrogen atom protein, and a 1.4-Å solvent probe, we in general underestimate the total solvent-accessible surface area (SASA) by approximately 1.25% with a correlation coefficient of 0.9990 over a wide range of conformations. The average CPU time required to calculate the SASA of a BPTI conformer is 0.58 s on an SGI 4D/220 workstation. We also describe a method by which we can calculate an approximate finite difference SASA gradient for BPTI in 0.79 of CPU time. © 1993 John Wiley & Sons, Inc.

Notes: A method is proposed for calculating the forces in path integral theory and tested on semiclassic systems. It takes the range of the classic and quantum interactions into account and uses a second table within the neighbors table for the nearest neighbors. This method is found to be much more efficient than either the standard direct method or the traditional neighbors table, the efficiency increasing with the size of the system. The method can also be applied to clusters whose interaction centers are much farther apart than the distances between two consecutive members of the cluster. © 1993 John Wiley & Sons, Inc.