Rationalizing the Relative Aggregability of Alpha-Synuclein Variants via Molecular Simulations

Abstract

The aberrant aggregation of α-Synuclein (αS), an intrinsically disordered protein, leads to a fatal neurodegenerative disease – Parkinson’s disease (PD). This study investigates the kinetics and thermodynamics of αS aggregation using extensive coarse-grained (CG) and atomistic simulations, implementing both conventional and enhanced sampling techniques. We examined the self-assembly of wild-type (WT) αS and its five abundant deleterious mutants (A30P, A53T, E46K, G51D, and H50Q) to understand their aggregation behaviour. αS mutants that alter charge (E46K, G51D, and H50Q) exhibit distinct trends in their relative rates of self-association and association with the WT chain. Among the neutral mutations, A30P dimerizes (either with itself or with WT aS) at a faster rate than A53T. The backbone contributes to the intra-chain hydrogen bond framework stability and the side chains dictate the inter-chain and protein-water interactions, possibly being more exposed. Whereas, the electrostatic and van der Waals forces specifically stabilize the intra-chain interactions over the inter-chain and protein-water talks – the former being the major protagonist. However, the pattern changes when the inter-chain binding affinity of the matured protofibrillar state is considered, compared to the initially aggregated constructs. One of the neutral mutations (A53T) and one of the chargealtering mutations (H50Q) show the highest and the lowest protofilament binding affinities (respectively) in homo-dimers, whereas E46K (a different charge-altering mutation) displays the highest binding affinity in hetero-dimers. Interestingly, the rate of association does not correlate with the protofilament binding affinity pattern, suggesting that faster aggregation does not necessarily lead to stable aggregates.