Small molecule modulates α-Synuclein conformation and its oligomerization via Entropy Expansion

Abstract

Aberrant misfolding and progressive aggregation of the intrinsically disordered protein (IDP), -synuclein, are associated with the etiology of several neurodegenerative diseases. However, the structurally heterogeneous ensemble of this IDP and lack of a well-defined binding pocket make it difficult to probe the druggability of -synuclein. Here, by building a comprehensive statistical model of the fuzzy ensemble of a millisecond-long atomistic simulation trajectory of monomeric -synuclein interacting with the small-molecule drug fasudil, we identify exhaustive sets of metastable binding-competent states of -synuclein. The model reveals that the interaction with the drug primes this IDP to explore both more compact and more extended conformational sub-ensemble than those in neat water, thereby broadening its structural repertoire in presence of small-molecule via an entropy expansion mechanism. Subsequent simulation of the dimerisation process shows that similar motif of entropic-expansion mechanism helps fasudil to retard the self-aggregation propensity of -synuclein via trapping it into multiple distinct states of diverse compaction featuring aggregation-resistant long-range interactions. Furthermore, small-molecule binding interactions in dimerisation-competent relatively extended states have a screening effect that hinders the formation of stable dimer contacts. Together, the investigation demonstrates the ability of small-molecules to have an ensemble-modulatory effect on IDPs that can be effectively utilised in therapeutic strategies probing aggregation-related diseases.