Structural Influence and Interactive Binding Behavior of Dopamine and Norepinephrine on the Greek-Key-Like Core of α-Synuclein Protofibril Revealed by Molecular Dynamics Simulations

The pathogenesis of Parkinson&rsquo:s disease (PD) is closely associated with the aggregation of &alpha:-synuclein (&alpha:S) protein. Finding the effective inhibitors of &alpha:S aggregation has been considered as the primary therapeutic strategy for PD. Recent studies reported that two neurotransmitters, dopamine (DA) and norepinephrine (NE), can effectively inhibit &alpha:S aggregation and disrupt the preformed &alpha:S fibrils. However, the atomistic details of &alpha:S-DA/NE interaction remain unclear. Here, using molecular dynamics simulations, we investigated the binding behavior of DA/NE molecules and their structural influence on &alpha:S44&ndash:96 (Greek-key-like core of full length &alpha:S) protofibrillar tetramer. Our results showed that DA/NE molecules destabilize &alpha:S protofibrillar tetramer by disrupting the &beta:-sheet structure and destroying the intra- and inter-peptide E46&ndash:K80 salt bridges, and they can also destroy the inter-chain backbone hydrogen bonds. Three binding sites were identified for both DA and NE molecules interacting with &alpha:S tetramer: T54&ndash:T72, Q79&ndash:A85, and F94&ndash:K96, and NE molecules had a stronger binding capacity to these sites than DA. The binding of DA/NE molecules to &alpha:S tetramer is dominantly driven by electrostatic and hydrogen bonding interactions. Through aromatic &pi:-stacking, DA and NE molecules can bind to &alpha:S protofibril interactively. Our work reveals the detailed disruptive mechanism of protofibrillar &alpha:S oligomer by DA/NE molecules, which is helpful for the development of drug candidates against PD. Given that exercise as a stressor can stimulate DA/NE secretion and elevated levels of DA/NE could delay the progress of PD, this work also enhances our understanding of the biological mechanism by which exercise prevents and alleviates PD.