An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein
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 struc...
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eLife Sciences Publications Ltd
2024-12-01
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| Online Access: | https://elifesciences.org/articles/97709 |
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| author | Sneha Menon Subinoy Adhikari Jagannath Mondal |
| author_facet | Sneha Menon Subinoy Adhikari Jagannath Mondal |
| author_sort | Sneha Menon |
| collection | DOAJ |
| description | 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-dependence in residue-wise interaction with the small molecule. A thermodynamic analysis indicates that small-molecule modulates the structural repertoire of αS by tuning protein backbone entropy, however entropy of the water remains unperturbed. Together, this study sheds light on the intricate interplay between small molecules and IDPs, offering insights into entropic modulation and ensemble expansion as key biophysical mechanisms driving potential therapeutics. |
| format | Article |
| id | doaj-art-3fdc90b371e34eb682e9f28a9d083d88 |
| institution | OA Journals |
| issn | 2050-084X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-3fdc90b371e34eb682e9f28a9d083d882025-08-20T01:58:05ZengeLife Sciences Publications LtdeLife2050-084X2024-12-011310.7554/eLife.97709An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synucleinSneha Menon0https://orcid.org/0000-0003-1079-8928Subinoy Adhikari1Jagannath Mondal2https://orcid.org/0000-0003-1090-5199Tata Institute of Fundamental Research, Hyderabad, IndiaTata Institute of Fundamental Research, Hyderabad, IndiaTata Institute of Fundamental Research, Hyderabad, IndiaThe 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-dependence in residue-wise interaction with the small molecule. A thermodynamic analysis indicates that small-molecule modulates the structural repertoire of αS by tuning protein backbone entropy, however entropy of the water remains unperturbed. Together, this study sheds light on the intricate interplay between small molecules and IDPs, offering insights into entropic modulation and ensemble expansion as key biophysical mechanisms driving potential therapeutics.https://elifesciences.org/articles/97709alpha synucleinsmall moleculemachine learning |
| spellingShingle | Sneha Menon Subinoy Adhikari Jagannath Mondal An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein eLife alpha synuclein small molecule machine learning |
| title | An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein |
| title_full | An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein |
| title_fullStr | An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein |
| title_full_unstemmed | An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein |
| title_short | An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein |
| title_sort | integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α synuclein |
| topic | alpha synuclein small molecule machine learning |
| url | https://elifesciences.org/articles/97709 |
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