An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein.

ABSTRACT: The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α-synuclein (αS) underlie the pathogenesis of various neurodegenerative disorders. However, targeting αS with small molecules faces challenges due to the lack of defined ligand-binding pockets in its disordered structure. Here, we implement a deep artificial neural network-based machine learning approach, which is able to statistically distinguish the fuzzy ensemble of conformational substates of αS in neat water from those in aqueous fasudil (small molecule of interest) solution. In particular, the presence of fasudil in the solvent either modulates pre-existing states of αS or gives rise to new conformational states of αS, akin to an ensemble-expansion mechanism. The ensembles display strong conformation-

SUBMITTER: Menon S 

PROVIDER: S-EPMC11655066 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature