Assessing the performance of three resveratrol in binding with SIRT1 by molecular dynamics simulation and MM/GBSA methods: the weakest binding of resveratrol 3 to SIRT1 triggers a possibility of dissociation from its binding site.

SIRT1 is an NAD+-dependent deacetylase, whose activators have potential therapeutic applications in the age-related, metabolic, neurode-generative and cardiovascular diseases. Resveratrol (RSV) has been regarded as potent SIRT1 activator in the treatment of atherosclerosis and cardiovascular diseases. Moreover, the previous crystal structure of SIRT1 complex with RSV indicated that three RSV participated in the SIRT1 activation, namely RSV1 and RSV2 strengthened the interaction of SIRT1 to its substrate peptide and promoted the stimulation of SIRT1 activity, while RSV3 exhibited an auxiliary function. Whereas the molecular mechanism of the insignificant role of RSV3 has not been reported. Moreover, the dynamics properties of three RSV in the binding site of SIRT1 are still unknown. In this study, to evaluate the role of RSV3 systematically, five SIRT1_RSV system (SIRT1_RSV1-3, SIRT1_RSV1-2, SIRT1_RSV1, 3, SIRT1_RSV2-3 and SIRT13) were constructed and subjected to 20 ns molecular dynamics simulation. Our simulations showed that the binding of RSV1 was extremely stable in any system and might be independent to the existence of RSV2 and RSV3. The stability of RSV2 was slightly weaker than that of RSV1. More interestingly, RSV3 could completely dissociate from its binding site in SIRT1_RSV1-3 system at 7 ns, which might be an important factor for its auxiliary role in activating SIRT1. Actually, some preliminary signs of RSV3 dissociation already appeared around 1 ns. In detail, the innate weakness between RSV3 and Lys444 would trigger frequent formation and breakage of the RSV3-Lys444 hydrogen bond. Residue Asp298 preferred to form hydrogen bond with RSV2 rather than RSV3 once the RSV3-Lys444 hydrogen bond became stronger. Without the RSV3-Asp298 interaction, the remaining RSV3-Lys444 and RSV3-Asp292 hydrogen bonds hardly preserved the RSV3's binding, which resulted in the dissociation of RSV3. Our work elucidated the inequable contributions of three RSV on their binding interaction with SIRT1 and indicated that the binding sites of RSV1 and RSV2 should be enough to design more potent SIRT1 activator.