ALBERT

Description: Background Mutation of amino acid sequences in a protein may have diverse effects on its structure and function. Point mutations ofeven a single amino acid residue in the helices of thenon-redundant database may lead to sequentially identical peptides whichadopt different secondary structures in different proteins. However, variousphysico-chemical factors which govern the formation of these ambivalent helices generated by point mutationsof a sequence are not clearly known.Results Sequences generated by point mutations of helices are mapped on to theirnon-helical counterparts in the SCOP database. The results show thatshort helices are prone to transform into non-helical conformations upon pointmutations. Mutation of amino acid residues by helix breakerspreferentially yield non-helical conformations, while mutation withresidues of intermediate helix propensity display least preferences fornon-helical conformations. Differences in the solvent accessibility of themutating/mutated residues are found to be a major criteria for these sequencesto conform to non-helical conformations. Even with minimal differencesin the amino acid distributions of the sequences flanking the helicaland non-helical conformations, helix-flanking sequences are found bemore solvent accessible.Conclusions All types of mutations from helicalto non-helical conformations are investigated. The primary factorsattributing such changes in conformation can be: i) type/propensity ofthe mutating and mutant residues ii) solvent accessibility of the residue at the mutation siteiii) context/environment dependence of the flanking sequences. Theresults from the present study may be used to design de novoproteins via point mutations.

Description: Background: Resveratrol, a naturally occurring stilbene, has been categorized as phytoestrogen due to its capability to compete with natural estrogens for binding to estrogen receptor alpha (ERalpha) and thus modulating the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERalpha) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results: Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERalpha ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERalpha monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERalpha in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERalpha dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERalpha are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERalpha. Conclusions: Our Molecular Dynamics simulation of RES-ERalpha structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.

Description: Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα. Conclusions Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity.