Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin
Transitions between different conformational states are ubiquitous in proteins, being involved in signaling, catalysis, and other fundamental activities in cells. However, modeling those processes is extremely difficult, due to the need of efficiently exploring a vast conformational space in order t...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2019.00104/full |
| _version_ | 1818308966847873024 |
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| author | Francesco Delfino Francesco Delfino Yuri Porozov Yuri Porozov Eugene Stepanov Eugene Stepanov Gaik Tamazian Valentina Tozzini |
| author_facet | Francesco Delfino Francesco Delfino Yuri Porozov Yuri Porozov Eugene Stepanov Eugene Stepanov Gaik Tamazian Valentina Tozzini |
| author_sort | Francesco Delfino |
| collection | DOAJ |
| description | Transitions between different conformational states are ubiquitous in proteins, being involved in signaling, catalysis, and other fundamental activities in cells. However, modeling those processes is extremely difficult, due to the need of efficiently exploring a vast conformational space in order to seek for the actual transition path for systems whose complexity is already high in the stable states. Here we report a strategy that simplifies this task attacking the complexity on several sides. We first apply a minimalist coarse-grained model to Calmodulin, based on an empirical force field with a partial structural bias, to explore the transition paths between the apo-closed state and the Ca-bound open state of the protein. We then select representative structures along the trajectory based on a structural clustering algorithm and build a cleaned-up trajectory with them. We finally compare this trajectory with that produced by the online tool MinActionPath, by minimizing the action integral using a harmonic network model, and with that obtained by the PROMPT morphing method, based on an optimal mass transportation-type approach including physical constraints. The comparison is performed both on the structural and energetic level, using the coarse-grained and the atomistic force fields upon reconstruction. Our analysis indicates that this method returns trajectories capable of exploring intermediate states with physical meaning, retaining a very low computational cost, which can allow systematic and extensive exploration of the multi-stable proteins transition pathways. |
| first_indexed | 2024-12-13T07:22:40Z |
| format | Article |
| id | doaj.art-7f1885ff0e89418a9f9cd08c55e7259e |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-13T07:22:40Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-7f1885ff0e89418a9f9cd08c55e7259e2022-12-21T23:55:23ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2019-10-01610.3389/fmolb.2019.00104471460Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to CalmodulinFrancesco Delfino0Francesco Delfino1Yuri Porozov2Yuri Porozov3Eugene Stepanov4Eugene Stepanov5Gaik Tamazian6Valentina Tozzini7I.M. Sechenov First Moscow State Medical University, Moscow, RussiaIstituto Nanoscienze – CNR and NEST-Scuola Normale Superiore, Pisa, ItalyI.M. Sechenov First Moscow State Medical University, Moscow, RussiaITMO University, St. Petersburg, RussiaSt. Petersburg Branch of the Steklov Mathematical Institute of the Russian Academy of Sciences, St. Petersburg, RussiaDepartment of Mathematical Physics, Faculty of Mathematics and Mechanics, St. Petersburg State University, St. Petersburg, RussiaTheodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St. Petersburg, RussiaIstituto Nanoscienze – CNR and NEST-Scuola Normale Superiore, Pisa, ItalyTransitions between different conformational states are ubiquitous in proteins, being involved in signaling, catalysis, and other fundamental activities in cells. However, modeling those processes is extremely difficult, due to the need of efficiently exploring a vast conformational space in order to seek for the actual transition path for systems whose complexity is already high in the stable states. Here we report a strategy that simplifies this task attacking the complexity on several sides. We first apply a minimalist coarse-grained model to Calmodulin, based on an empirical force field with a partial structural bias, to explore the transition paths between the apo-closed state and the Ca-bound open state of the protein. We then select representative structures along the trajectory based on a structural clustering algorithm and build a cleaned-up trajectory with them. We finally compare this trajectory with that produced by the online tool MinActionPath, by minimizing the action integral using a harmonic network model, and with that obtained by the PROMPT morphing method, based on an optimal mass transportation-type approach including physical constraints. The comparison is performed both on the structural and energetic level, using the coarse-grained and the atomistic force fields upon reconstruction. Our analysis indicates that this method returns trajectories capable of exploring intermediate states with physical meaning, retaining a very low computational cost, which can allow systematic and extensive exploration of the multi-stable proteins transition pathways.https://www.frontiersin.org/article/10.3389/fmolb.2019.00104/fullproteins conformational transitionsclassical molecular dynamicscoarse grained modelstransition path samplingminimal action pathPROMPT |
| spellingShingle | Francesco Delfino Francesco Delfino Yuri Porozov Yuri Porozov Eugene Stepanov Eugene Stepanov Gaik Tamazian Valentina Tozzini Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin Frontiers in Molecular Biosciences proteins conformational transitions classical molecular dynamics coarse grained models transition path sampling minimal action path PROMPT |
| title | Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin |
| title_full | Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin |
| title_fullStr | Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin |
| title_full_unstemmed | Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin |
| title_short | Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin |
| title_sort | structural transition states explored with minimalist coarse grained models applications to calmodulin |
| topic | proteins conformational transitions classical molecular dynamics coarse grained models transition path sampling minimal action path PROMPT |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2019.00104/full |
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