Molecular Modeling of the Aggregation and Disaggregation Processes of α‐Synuclein: An Important Biomarker of parkinson's Disease

Abstract Molecular modeling techniques is applied to investigate the mechanisms of α‐Syn aggregation, analyzing the stability of oligomers, as well as evaluating the potential of polyphenols in destabilizing these aggregates. The results indicate that the stability of the aggregates increases with the number of peptide chains, due to the formation of secondary structures in α‐Syn, particularly β‐sheets. Among the models studied, the tetramer is identified as the smallest stable protofibril, making it a target for ligand testing. Regarding the interaction analysis between polyphenols and α‐Syn aggregates, molecular dynamics simulations suggest that quercetin (QC) and hydroxytyrosol (HT), and genistein (GT) interact in the NAC region of the oligomer. Furthermore, the analysis of the total contacts fraction revealed that the presence of the ligand reduces the number of residue‐residue interactions within the oligomer, suggesting a global destabilizing effect on the aggregate structure. In terms of energetic parameters, QC showed the greatest destabilizing effect, followed by GT. HT, in turn, exhibited a localized destabilizing effect. Thus, the present study provides insights into the destabilization of the α‐Syn tetramer by polyphenols, which may contribute to the development of new therapies for Parkinson's disease.