Direct coupling analysis of epistasis in allosteric materials
Autor(a) principal: | |
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Data de Publicação: | 2020 |
Outros Autores: | , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFRGS |
Texto Completo: | http://hdl.handle.net/10183/212577 |
Resumo: | In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug design, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in particular on the existence of long-range evolutionary couplings between distant amino-acids mediating allostery. Here we propose a resolution of this conundrum, by studying epistasis and its inference in models where an allosteric material is evolved in silico to perform a mechanical task. We find in our model the four types of epistasis (Synergistic, Sign, Antagonistic, Saturation), which can be both short or long-range and have a simple mechanical interpretation. We perform a Direct Coupling Analysis (DCA) and find that DCA predicts well the cost of point mutations but is a rather poor generative model. Strikingly, it can predict short-range epistasis but fails to capture long-range epistasis, in consistence with empirical findings. We propose that such failure is generic when function requires subparts to work in concert. We illustrate this idea with a simple model, which suggests that other methods may be better suited to capture long-range effects. |
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Bravi, BarbaraRavasio, RiccardoBrito, CarolinaWyart, Matthieu2020-08-04T03:38:38Z20201553-734Xhttp://hdl.handle.net/10183/212577001115523In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug design, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in particular on the existence of long-range evolutionary couplings between distant amino-acids mediating allostery. Here we propose a resolution of this conundrum, by studying epistasis and its inference in models where an allosteric material is evolved in silico to perform a mechanical task. We find in our model the four types of epistasis (Synergistic, Sign, Antagonistic, Saturation), which can be both short or long-range and have a simple mechanical interpretation. We perform a Direct Coupling Analysis (DCA) and find that DCA predicts well the cost of point mutations but is a rather poor generative model. Strikingly, it can predict short-range epistasis but fails to capture long-range epistasis, in consistence with empirical findings. We propose that such failure is generic when function requires subparts to work in concert. We illustrate this idea with a simple model, which suggests that other methods may be better suited to capture long-range effects.application/pdfengPLoS computational biology. San Francisco. Vol. 16, no. 3 (Mar. 2020), e1003482, 19 p.ProteínasRegulação alostéricaEpistasia genéticaDirect coupling analysis of epistasis in allosteric materialsEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001115523.pdf.txt001115523.pdf.txtExtracted Texttext/plain65154http://www.lume.ufrgs.br/bitstream/10183/212577/2/001115523.pdf.txt68de74b7466327b0adf828e4ac970e23MD52ORIGINAL001115523.pdfTexto completo (inglês)application/pdf2397053http://www.lume.ufrgs.br/bitstream/10183/212577/1/001115523.pdf16ce0c1e6ca267dfc23454a7617a0913MD5110183/2125772020-08-05 03:39:03.755122oai:www.lume.ufrgs.br:10183/212577Repositório de PublicaçõesPUBhttps://lume.ufrgs.br/oai/requestopendoar:2020-08-05T06:39:03Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false |
dc.title.pt_BR.fl_str_mv |
Direct coupling analysis of epistasis in allosteric materials |
title |
Direct coupling analysis of epistasis in allosteric materials |
spellingShingle |
Direct coupling analysis of epistasis in allosteric materials Bravi, Barbara Proteínas Regulação alostérica Epistasia genética |
title_short |
Direct coupling analysis of epistasis in allosteric materials |
title_full |
Direct coupling analysis of epistasis in allosteric materials |
title_fullStr |
Direct coupling analysis of epistasis in allosteric materials |
title_full_unstemmed |
Direct coupling analysis of epistasis in allosteric materials |
title_sort |
Direct coupling analysis of epistasis in allosteric materials |
author |
Bravi, Barbara |
author_facet |
Bravi, Barbara Ravasio, Riccardo Brito, Carolina Wyart, Matthieu |
author_role |
author |
author2 |
Ravasio, Riccardo Brito, Carolina Wyart, Matthieu |
author2_role |
author author author |
dc.contributor.author.fl_str_mv |
Bravi, Barbara Ravasio, Riccardo Brito, Carolina Wyart, Matthieu |
dc.subject.por.fl_str_mv |
Proteínas Regulação alostérica Epistasia genética |
topic |
Proteínas Regulação alostérica Epistasia genética |
description |
In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug design, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in particular on the existence of long-range evolutionary couplings between distant amino-acids mediating allostery. Here we propose a resolution of this conundrum, by studying epistasis and its inference in models where an allosteric material is evolved in silico to perform a mechanical task. We find in our model the four types of epistasis (Synergistic, Sign, Antagonistic, Saturation), which can be both short or long-range and have a simple mechanical interpretation. We perform a Direct Coupling Analysis (DCA) and find that DCA predicts well the cost of point mutations but is a rather poor generative model. Strikingly, it can predict short-range epistasis but fails to capture long-range epistasis, in consistence with empirical findings. We propose that such failure is generic when function requires subparts to work in concert. We illustrate this idea with a simple model, which suggests that other methods may be better suited to capture long-range effects. |
publishDate |
2020 |
dc.date.accessioned.fl_str_mv |
2020-08-04T03:38:38Z |
dc.date.issued.fl_str_mv |
2020 |
dc.type.driver.fl_str_mv |
Estrangeiro info:eu-repo/semantics/article |
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info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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http://hdl.handle.net/10183/212577 |
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1553-734X |
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001115523 |
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http://hdl.handle.net/10183/212577 |
dc.language.iso.fl_str_mv |
eng |
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eng |
dc.relation.ispartof.pt_BR.fl_str_mv |
PLoS computational biology. San Francisco. Vol. 16, no. 3 (Mar. 2020), e1003482, 19 p. |
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info:eu-repo/semantics/openAccess |
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openAccess |
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