An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein DOI Creative Commons
Sneha Menon,

Subinoy Adhikari,

Jagannath Mondal

и другие.

eLife, Год журнала: 2024, Номер 13

Опубликована: Июнь 3, 2024

The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α-synuclein (αS) underlie the pathogenesis various neurodegenerative disorders. However, targeting αS with small molecules faces challenges due to lack defined ligand-binding pockets in its structure. Here, we implement a deep artificial neural network-based machine learning approach, which is able statistically distinguish fuzzy ensemble conformational substates neat water from those aqueous fasudil (small molecule interest) solution. In particular, presence solvent either modulates pre-existing states or gives rise new αS, akin an ensemble-expansion mechanism. ensembles display strong conformation-dependence residue-wise interaction molecule. A thermodynamic analysis indicates that small-molecule structural repertoire by tuning protein backbone entropy, however entropy remains unperturbed. Together, this study sheds light on intricate interplay between IDPs, offering insights into entropic modulation expansion key biophysical mechanisms driving potential therapeutics.

Язык: Английский

An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein DOI Creative Commons
Sneha Menon,

Subinoy Adhikari,

Jagannath Mondal

и другие.

eLife, Год журнала: 2024, Номер 13

Опубликована: Июнь 3, 2024

The mis-folding and aggregation of intrinsically disordered proteins (IDPs) such as α-synuclein (αS) underlie the pathogenesis various neurodegenerative disorders. However, targeting αS with small molecules faces challenges due to lack defined ligand-binding pockets in its structure. Here, we implement a deep artificial neural network-based machine learning approach, which is able statistically distinguish fuzzy ensemble conformational substates neat water from those aqueous fasudil (small molecule interest) solution. In particular, presence solvent either modulates pre-existing states or gives rise new αS, akin an ensemble-expansion mechanism. ensembles display strong conformation-dependence residue-wise interaction molecule. A thermodynamic analysis indicates that small-molecule structural repertoire by tuning protein backbone entropy, however entropy remains unperturbed. Together, this study sheds light on intricate interplay between IDPs, offering insights into entropic modulation expansion key biophysical mechanisms driving potential therapeutics.

Язык: Английский

Процитировано

1