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.