Structural and Dynamical Characterization of α-Synuclein A53T Mutation: Implications for Misfolding Inhibition by NPT200-11

This report presents a molecular dynamics (MD)–based structural and dynamical analysis of α-synuclein carrying the A53T mutation, with direct relevance to therapeutic strategies based onmisfolding inhibitors such as NPT200-11. Rather than focusing on aggregation endpoints alone, we analyze the early dynamical instabilities that precede misfolding, using wild-type (WT) α-synuclein as a structural and dynamical reference. Our results indicate that the A53T mutation introduces localized increases in conformational flexibility and transient loss of intra-regional contacts, particularly in the 45–65 region, generating a vulnerable dynamical regime that is consistent with increased aggregation propensity. These findings suggest a mechanistic framework in which small molecules such as NPT200-11 may exert their protective effects by stabilizing specific conformational sub-ensembles rather than globally suppressing aggregation. Lab website: functionaldynamicslab.org.yzz.me Collaboration email: functionaldynamicslab@proton.me