Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation
Abstract The bottleneck in enhanced sampling lies in finding collective variables that effectively accelerate protein conformational changes; true reaction coordinates that accurately predict the committor are the well-recognized optimal choice. However, identifying them requires unbiased natural re...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55983-y |
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| _version_ | 1832594533219565568 |
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| author | Huiyu Li Ao Ma |
| author_facet | Huiyu Li Ao Ma |
| author_sort | Huiyu Li |
| collection | DOAJ |
| description | Abstract The bottleneck in enhanced sampling lies in finding collective variables that effectively accelerate protein conformational changes; true reaction coordinates that accurately predict the committor are the well-recognized optimal choice. However, identifying them requires unbiased natural reactive trajectories, which, paradoxically, require effective enhanced sampling. Using the generalized work functional method, we uncover that true reaction coordinates control both conformational changes and energy relaxation, enabling us to compute them from energy relaxation simulations. Biasing true reaction coordinates accelerates conformational changes and ligand dissociation in PDZ2 domain and HIV-1 protease by 105 to 1015-fold. The resulting trajectories follow natural transition pathways, enabling efficient generation of unbiased reactive trajectories. In contrast, biased trajectories from empirical collective variables display non-physical features. Furthermore, our method uses a single protein structure as input, enabling predictive sampling of conformational changes. These findings unlock access to a broader range of protein functional processes in molecular dynamics simulations. |
| format | Article |
| id | doaj-art-20956af0bbca48f0a23ae5103e5096cc |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-20956af0bbca48f0a23ae5103e5096cc2025-01-19T12:31:47ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-025-55983-yEnhanced sampling of protein conformational changes via true reaction coordinates from energy relaxationHuiyu Li0Ao Ma1Center for Bioinformatics and Quantitative Biology, Richard and Loan Hill Department of Biomedical Engineering, The University of Illinois Chicago, 851 South Morgan StreetCenter for Bioinformatics and Quantitative Biology, Richard and Loan Hill Department of Biomedical Engineering, The University of Illinois Chicago, 851 South Morgan StreetAbstract The bottleneck in enhanced sampling lies in finding collective variables that effectively accelerate protein conformational changes; true reaction coordinates that accurately predict the committor are the well-recognized optimal choice. However, identifying them requires unbiased natural reactive trajectories, which, paradoxically, require effective enhanced sampling. Using the generalized work functional method, we uncover that true reaction coordinates control both conformational changes and energy relaxation, enabling us to compute them from energy relaxation simulations. Biasing true reaction coordinates accelerates conformational changes and ligand dissociation in PDZ2 domain and HIV-1 protease by 105 to 1015-fold. The resulting trajectories follow natural transition pathways, enabling efficient generation of unbiased reactive trajectories. In contrast, biased trajectories from empirical collective variables display non-physical features. Furthermore, our method uses a single protein structure as input, enabling predictive sampling of conformational changes. These findings unlock access to a broader range of protein functional processes in molecular dynamics simulations.https://doi.org/10.1038/s41467-025-55983-y |
| spellingShingle | Huiyu Li Ao Ma Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation Nature Communications |
| title | Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| title_full | Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| title_fullStr | Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| title_full_unstemmed | Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| title_short | Enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| title_sort | enhanced sampling of protein conformational changes via true reaction coordinates from energy relaxation |
| url | https://doi.org/10.1038/s41467-025-55983-y |
| work_keys_str_mv | AT huiyuli enhancedsamplingofproteinconformationalchangesviatruereactioncoordinatesfromenergyrelaxation AT aoma enhancedsamplingofproteinconformationalchangesviatruereactioncoordinatesfromenergyrelaxation |