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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...

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Autores principales: Stein, Richard A., Mchaourab, Hassane S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
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.
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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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