Consistent Force Field Captures Homolog Resolved HP1 Phase Separation
Many proteins have been shown to function via liquid-liquid phase separation. Computational modeling could offer much needed structural details of protein condensates and reveal the set of molecular interactions that dictate their stability. However, the presence of both ordered and disordered domai...
| Main Authors: | , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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American Chemical Society (ACS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/141345.2 |
| _version_ | 1811096346601455616 |
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| author | Latham, Andrew P Zhang, Bin |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Latham, Andrew P Zhang, Bin |
| author_sort | Latham, Andrew P |
| collection | MIT |
| description | Many proteins have been shown to function via liquid-liquid phase separation. Computational modeling could offer much needed structural details of protein condensates and reveal the set of molecular interactions that dictate their stability. However, the presence of both ordered and disordered domains in these proteins places a high demand on the model accuracy. Here, we present an algorithm to derive a coarse-grained force field, MOFF, which can model both ordered and disordered proteins with consistent accuracy. It combines maximum entropy biasing, least-squares fitting, and basic principles of energy landscape theory to ensure that MOFF recreates experimental radii of gyration while predicting the folded structures for globular proteins with lower energy. The theta temperature determined from MOFF separates ordered and disordered proteins at 300 K and exhibits a strikingly linear relationship with amino acid sequence composition. We further applied MOFF to study the phase behavior of HP1, an essential protein for post-translational modification and spatial organization of chromatin. The force field successfully resolved the structural difference of two HP1 homologues despite their high sequence similarity. We carried out large-scale simulations with hundreds of proteins to determine the critical temperature of phase separation and uncover multivalent interactions that stabilize higher-order assemblies. In all, our work makes significant methodological strides to connect theories of ordered and disordered proteins and provides a powerful tool for studying liquid-liquid phase separation with near-atomistic details. |
| first_indexed | 2024-09-23T16:42:23Z |
| format | Article |
| id | mit-1721.1/141345.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:42:23Z |
| publishDate | 2022 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/141345.22022-03-24T16:17:45Z Consistent Force Field Captures Homolog Resolved HP1 Phase Separation Consistent Force Field Captures Homologue-Resolved HP1 Phase Separation Latham, Andrew P Zhang, Bin Massachusetts Institute of Technology. Department of Chemistry Many proteins have been shown to function via liquid-liquid phase separation. Computational modeling could offer much needed structural details of protein condensates and reveal the set of molecular interactions that dictate their stability. However, the presence of both ordered and disordered domains in these proteins places a high demand on the model accuracy. Here, we present an algorithm to derive a coarse-grained force field, MOFF, which can model both ordered and disordered proteins with consistent accuracy. It combines maximum entropy biasing, least-squares fitting, and basic principles of energy landscape theory to ensure that MOFF recreates experimental radii of gyration while predicting the folded structures for globular proteins with lower energy. The theta temperature determined from MOFF separates ordered and disordered proteins at 300 K and exhibits a strikingly linear relationship with amino acid sequence composition. We further applied MOFF to study the phase behavior of HP1, an essential protein for post-translational modification and spatial organization of chromatin. The force field successfully resolved the structural difference of two HP1 homologues despite their high sequence similarity. We carried out large-scale simulations with hundreds of proteins to determine the critical temperature of phase separation and uncover multivalent interactions that stabilize higher-order assemblies. In all, our work makes significant methodological strides to connect theories of ordered and disordered proteins and provides a powerful tool for studying liquid-liquid phase separation with near-atomistic details. NIH (Grant 1R35GM133580) NSF (Grant MCB-2042362) 2022-03-24T16:17:44Z 2022-03-23T16:06:32Z 2022-03-24T16:17:44Z 2021 2022-03-23T16:01:22Z Article http://purl.org/eprint/type/JournalArticle 1549-9626 https://hdl.handle.net/1721.1/141345.2 Latham, Andrew P and Zhang, Bin. 2021. "Consistent Force Field Captures Homologue-Resolved HP1 Phase Separation." Journal of Chemical Theory and Computation, 17 (5). en https://dx.doi.org/10.1021/acs.jctc.0c01220 Journal of Chemical Theory and Computation Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/octet-stream American Chemical Society (ACS) PMC |
| spellingShingle | Latham, Andrew P Zhang, Bin Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title | Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title_full | Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title_fullStr | Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title_full_unstemmed | Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title_short | Consistent Force Field Captures Homolog Resolved HP1 Phase Separation |
| title_sort | consistent force field captures homolog resolved hp1 phase separation |
| url | https://hdl.handle.net/1721.1/141345.2 |
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