Molecular dynamics simulation characteristics of resveratrol interaction with human estrogen receptor-α:: distinct recognition from diethylstilbestrol

Resveratrol (RSVL) is a phytoestrogen that claims numerous health benefits and structural similarity to the estrogen receptor-alpha (ERalpha) agonist diethylstilbestrol (DES). Surprisingly, RSVL displayed agonist/antagonist profiles in estrogen-responsive biological systems. Underpinnings of such actions remain poorly understood. In absence of a known crystal structure for RSVL-ERalpha, all possible orientations for the lowest energy conformer of RSVL have been considered. These modes were evaluated based on recognition by the ERalpha binding-pocket with respect to binding energy, hydrogen bonding, root-mean-square deviation (RMSd) values of active-site residues, and differences in conformational energy (DeltaE). These studies rigorously favored one RSVL orientation as the binding conformation (RSVL-a). The differential binding characteristics of (RSVL-a) and DES were comparatively evaluated throughout a 100 ps molecular dynamics (MD) simulation with the ERalpha. The two DES hydroxyl (OH) groups contributed three stable hydrogen bonds with the 'catalytic triad' residues of ERalpha pocket. The 4'-OH of ring-A conferred two H-bonds with Arg394, Glu353, whereas the 4-OH of ring-B formed one H-bond with His524. By contrast, RSVL-a displayed a more intricate profile in which six H-bonds were formed that involved all three RSVL-OH groups. The 4'-OH of ring-A formed trifurcated H-bonds with Arg394, Glu353 and Phe404. The 3-OH of ring-B contributed one H-bond with Met343. The 5-OH was linked to both Gly521, Leu524 and His524, the latter H-bond persisted for only 60 ps. Following dynamics simulation, DES and RSVL-a displayed considerable differences in their binding energy and free energy of solvation/desolvation. Finally, RSVL and DES triggered disparable patterns of movement for key pocket residues (RMSd scores). Conclusively, the present study suggests that RSVL is well recognized by the human ERalpha; however, in a highly distinct manner from the pure agonist DES. These dynamic, electrostatic and catalytic differences may well explain the altered responsiveness to RSVL in ER-endowed biological systems. (C) 2002 Elsevier Science B.V. All rights reserved.