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Media type:
E-Article
Title:
SPEACH_AF: Sampling protein ensembles and conformational heterogeneity with Alphafold2
Contributor:
Stein, Richard A.;
Mchaourab, Hassane S.
imprint:
Public Library of Science (PLoS), 2022
Published in:PLOS Computational Biology
Language:
English
DOI:
10.1371/journal.pcbi.1010483
ISSN:
1553-7358
Origination:
Footnote:
Description:
<jats:p>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 <jats:italic>in silico</jats:italic> 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.</jats:p>