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SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2
The unprecedented performance of Deepmind’s Alphafold2 in predicting protein structure in CASP XIV and the creation of a database of structures for multiple proteomes and protein sequence repositories is reshaping structural biology. However, because this database returns a single structure, it brou...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436118/ https://www.ncbi.nlm.nih.gov/pubmed/35994486 http://dx.doi.org/10.1371/journal.pcbi.1010483 |
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author | Stein, Richard A. Mchaourab, Hassane S. |
author_facet | Stein, Richard A. Mchaourab, Hassane S. |
author_sort | Stein, Richard A. |
collection | PubMed |
description | The unprecedented performance of Deepmind’s Alphafold2 in predicting protein structure in CASP XIV and the creation of a database of structures for multiple proteomes and protein sequence repositories is reshaping structural biology. However, because this database returns a single structure, it brought into question Alphafold’s ability to capture the intrinsic conformational flexibility of proteins. Here we present a general approach to drive Alphafold2 to model alternate protein conformations through simple manipulation of the multiple sequence alignment via in silico mutagenesis. The approach is grounded in the hypothesis that the multiple sequence alignment must also encode for protein structural heterogeneity, thus its rational manipulation will enable Alphafold2 to sample alternate conformations. A systematic modeling pipeline is benchmarked against canonical examples of protein conformational flexibility and applied to interrogate the conformational landscape of membrane proteins. This work broadens the applicability of Alphafold2 by generating multiple protein conformations to be tested biologically, biochemically, biophysically, and for use in structure-based drug design. |
format | Online Article Text |
id | pubmed-9436118 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94361182022-09-02 SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 Stein, Richard A. Mchaourab, Hassane S. PLoS Comput Biol Research Article The unprecedented performance of Deepmind’s Alphafold2 in predicting protein structure in CASP XIV and the creation of a database of structures for multiple proteomes and protein sequence repositories is reshaping structural biology. However, because this database returns a single structure, it brought into question Alphafold’s ability to capture the intrinsic conformational flexibility of proteins. Here we present a general approach to drive Alphafold2 to model alternate protein conformations through simple manipulation of the multiple sequence alignment via in silico mutagenesis. The approach is grounded in the hypothesis that the multiple sequence alignment must also encode for protein structural heterogeneity, thus its rational manipulation will enable Alphafold2 to sample alternate conformations. A systematic modeling pipeline is benchmarked against canonical examples of protein conformational flexibility and applied to interrogate the conformational landscape of membrane proteins. This work broadens the applicability of Alphafold2 by generating multiple protein conformations to be tested biologically, biochemically, biophysically, and for use in structure-based drug design. Public Library of Science 2022-08-22 /pmc/articles/PMC9436118/ /pubmed/35994486 http://dx.doi.org/10.1371/journal.pcbi.1010483 Text en © 2022 Stein, Mchaourab https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Stein, Richard A. Mchaourab, Hassane S. SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title | SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title_full | SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title_fullStr | SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title_full_unstemmed | SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title_short | SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2 |
title_sort | speach_af: sampling protein ensembles and conformational heterogeneity with alphafold2 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436118/ https://www.ncbi.nlm.nih.gov/pubmed/35994486 http://dx.doi.org/10.1371/journal.pcbi.1010483 |
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