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bioRxiv · 10.1101/2023.10.19.563053

Modulation of Liquid-liquid Phase separation of alpha-Synuclein by Saline and Crowded Environment

Wasim, A.·Menon, S.·Mondal, J.
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Abstract

Intrinsically disordered protein -Synuclein (S) is implicated in Parkinsons 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 of S in aqueous as well as under diverse environmental perturbations. In particular, the aggregation of S in aqueous and varied environmental condition led to marked concentration differences within protein aggregates, resembling liquid-liquid phase separation (LLPS). Both saline and crowded settings enhanced the LLPS propensity. However, the surface tension of S 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 perpendicular 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 of S, fostering inter-chain residue-residue interactions. Intriguingly, a graph theory analysis identifies small-world-like networks within 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 of S.

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Wasim, A., Menon, S., Mondal, J.. 2023-10-21. Modulation of Liquid-liquid Phase separation of alpha-Synuclein by Saline and Crowded Environment. https://doi.org/10.1101/2023.10.19.563053

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