Insights Into Resveratrol as an Inhibitor Against Aβ1-42 Peptide Aggregation: A Molecular Dynamics Simulation Study

Background: Resveratrol (RSV), a polyphenolic compound, is reported to have antiaggregation properties against Amyloid-beta peptides. It is, therefore, significant to understand the mechanism of inhibition of Aβ1-42 peptide aggregation by the RSV at the molecular level. We have used Molecular docking along with Molecular dynamics (MD) simulation techniques to address the role of RSV in the inhibition of Aβ1-42 peptide aggregation. Objective: To understand the role of Resveratrol on the Aβ1-42 peptide aggregation. Methods: In this computational study, we have docked the RSV to Aβ1-42 peptide using Molecular Docking software and then performed MD simulation for the Aβ1-42 peptide monomer Aβ1-42 peptide- RSV complex using the AMBER force field. From the analysis of MD trajectories, we obtained salient structural features and determined the Binding Free Energy(BFE) and Per-residue Energy Decomposition Analysis (PRED) using MM-PBSA/GBSA method. Results: The secondary structure and the conformational analysis obtained from MD trajectories show that the binding of RSV with the Aβ1-42 peptide monomer causes an increase in the helical content in the structure of the Aβ1-42 peptide. The BFE and PRED results show a high binding affinity (GBtotal=- 11.07 kcal mol^-1; PBtotal= -1.82 kcal mol^-1) of RSV with Aβ1-42 peptide. Also, we found the RSV to interact with crucial residues (Asp 23 and Lys 28) of the Aβ1-42 peptide. These residues play a significant role in facilitating the formation of toxic amyloid oligomers and amyloid fibrils. The salt bridge interaction between these residues D23-K28 was found to be destabilized in the Aβ1-42 peptide when it is complexed with RSV. Conclusion: In summary, it can be concluded that Resveratrol greatly aids the prevention of Aβ1-42 peptide aggregation. Therefore, it can be considered a possible drug candidate for therapeutic strategies for Alzheimer’s disease.