Author:
Wasim Abdul,Menon Sneha,Mondal Jagannath
Abstract
AbstractIntrinsically disordered proteinα-Synuclein (αS) is implicated in Parkinson’s disease due to its aberrant aggregation propensity. In a bid to identify the traits of its aggregation, here we computationally simulate the multi-chain association process ofαS in aqueous as well as under diverse environmental perturbations. In particular, the aggregation ofαS in aqueous and varied environmental condition led to marked concen-tration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension ofαS droplet responds differently to crowders (entropy-driven) and salt (enthalpy-driven). Conformational analysis reveals that the IDP chains would adopt extended conformations within aggregates and would maintain mutually per-pendicular orientations to minimize inter-chain electrostatic repulsions. The droplet stability is found to stem from a diminished intra-chain interactions in the C-terminal regions ofαS, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifiessmall-world-like networkswithin droplets across environmental conditions, suggesting the prevalence of a consensus interaction patterns among the chains. Together these findings suggest a delicate balance between molecular grammar and environment-dependent nuanced aggregation behaviour ofαS.
Publisher
Cold Spring Harbor Laboratory