Predicting substitutions to modulate disorder and stability in coiled-coils
Abstract Background Coiled-coils are described as stable structural motifs, where two or more helices wind around each other. However, coiled-coils are associated with local mobility and intrinsic disorder. Intrinsically disordered regions in proteins are characterized by lack of stable secondary an...
| Main Authors: | , , , , , , |
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| Format: | Article |
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BMC
2020-12-01
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| Series: | BMC Bioinformatics |
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| Online Access: | https://doi.org/10.1186/s12859-020-03867-x |
| _version_ | 1818611505019486208 |
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| author | Yasaman Karami Paul Saighi Rémy Vanderhaegen Denis Gerlier Sonia Longhi Elodie Laine Alessandra Carbone |
| author_facet | Yasaman Karami Paul Saighi Rémy Vanderhaegen Denis Gerlier Sonia Longhi Elodie Laine Alessandra Carbone |
| author_sort | Yasaman Karami |
| collection | DOAJ |
| description | Abstract Background Coiled-coils are described as stable structural motifs, where two or more helices wind around each other. However, coiled-coils are associated with local mobility and intrinsic disorder. Intrinsically disordered regions in proteins are characterized by lack of stable secondary and tertiary structure under physiological conditions in vitro. They are increasingly recognized as important for protein function. However, characterizing their behaviour in solution and determining precisely the extent of disorder of a protein region remains challenging, both experimentally and computationally. Results In this work, we propose a computational framework to quantify the extent of disorder within a coiled-coil in solution and to help design substitutions modulating such disorder. Our method relies on the analysis of conformational ensembles generated by relatively short all-atom Molecular Dynamics (MD) simulations. We apply it to the phosphoprotein multimerisation domains (PMD) of Measles virus (MeV) and Nipah virus (NiV), both forming tetrameric left-handed coiled-coils. We show that our method can help quantify the extent of disorder of the C-terminus region of MeV and NiV PMDs from MD simulations of a few tens of nanoseconds, and without requiring an extensive exploration of the conformational space. Moreover, this study provided a conceptual framework for the rational design of substitutions aimed at modulating the stability of the coiled-coils. By assessing the impact of four substitutions known to destabilize coiled-coils, we derive a set of rules to control MeV PMD structural stability and cohesiveness. We therefore design two contrasting substitutions, one increasing the stability of the tetramer and the other increasing its flexibility. Conclusions Our method can be considered as a platform to reason about how to design substitutions aimed at regulating flexibility and stability. |
| first_indexed | 2024-12-16T15:31:23Z |
| format | Article |
| id | doaj.art-c4b97fa0ca044aaea8f46b21eb323d2d |
| institution | Directory Open Access Journal |
| issn | 1471-2105 |
| language | English |
| last_indexed | 2024-12-16T15:31:23Z |
| publishDate | 2020-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Bioinformatics |
| spelling | doaj.art-c4b97fa0ca044aaea8f46b21eb323d2d2022-12-21T22:26:21ZengBMCBMC Bioinformatics1471-21052020-12-0121S1912010.1186/s12859-020-03867-xPredicting substitutions to modulate disorder and stability in coiled-coilsYasaman Karami0Paul Saighi1Rémy Vanderhaegen2Denis Gerlier3Sonia Longhi4Elodie Laine5Alessandra Carbone6CNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Sorbonne UniversitéCNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Sorbonne UniversitéCNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Sorbonne UniversitéCIRI, International Center for Infectiology Research, INSERM, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Univ LyonCNRS, Architecture et Fonction des Macromolécules Biologiques (AFMB), UMR 7257, Aix-Marseille UniversityCNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Sorbonne UniversitéCNRS, IBPS, UMR 7238, Laboratoire de Biologie Computationnelle et Quantitative (LCQB), Sorbonne UniversitéAbstract Background Coiled-coils are described as stable structural motifs, where two or more helices wind around each other. However, coiled-coils are associated with local mobility and intrinsic disorder. Intrinsically disordered regions in proteins are characterized by lack of stable secondary and tertiary structure under physiological conditions in vitro. They are increasingly recognized as important for protein function. However, characterizing their behaviour in solution and determining precisely the extent of disorder of a protein region remains challenging, both experimentally and computationally. Results In this work, we propose a computational framework to quantify the extent of disorder within a coiled-coil in solution and to help design substitutions modulating such disorder. Our method relies on the analysis of conformational ensembles generated by relatively short all-atom Molecular Dynamics (MD) simulations. We apply it to the phosphoprotein multimerisation domains (PMD) of Measles virus (MeV) and Nipah virus (NiV), both forming tetrameric left-handed coiled-coils. We show that our method can help quantify the extent of disorder of the C-terminus region of MeV and NiV PMDs from MD simulations of a few tens of nanoseconds, and without requiring an extensive exploration of the conformational space. Moreover, this study provided a conceptual framework for the rational design of substitutions aimed at modulating the stability of the coiled-coils. By assessing the impact of four substitutions known to destabilize coiled-coils, we derive a set of rules to control MeV PMD structural stability and cohesiveness. We therefore design two contrasting substitutions, one increasing the stability of the tetramer and the other increasing its flexibility. Conclusions Our method can be considered as a platform to reason about how to design substitutions aimed at regulating flexibility and stability.https://doi.org/10.1186/s12859-020-03867-xProtein structureProtein dynamicsCoiled-coilMolecular dynamicsProtein disorderProtein stability |
| spellingShingle | Yasaman Karami Paul Saighi Rémy Vanderhaegen Denis Gerlier Sonia Longhi Elodie Laine Alessandra Carbone Predicting substitutions to modulate disorder and stability in coiled-coils BMC Bioinformatics Protein structure Protein dynamics Coiled-coil Molecular dynamics Protein disorder Protein stability |
| title | Predicting substitutions to modulate disorder and stability in coiled-coils |
| title_full | Predicting substitutions to modulate disorder and stability in coiled-coils |
| title_fullStr | Predicting substitutions to modulate disorder and stability in coiled-coils |
| title_full_unstemmed | Predicting substitutions to modulate disorder and stability in coiled-coils |
| title_short | Predicting substitutions to modulate disorder and stability in coiled-coils |
| title_sort | predicting substitutions to modulate disorder and stability in coiled coils |
| topic | Protein structure Protein dynamics Coiled-coil Molecular dynamics Protein disorder Protein stability |
| url | https://doi.org/10.1186/s12859-020-03867-x |
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