AI Article Synopsis
- DeepMind's AlphaFold2 has revolutionized structural biology by accurately predicting protein structures and creating a comprehensive database, but it typically provides only a single conformation, raising concerns about its ability to represent protein flexibility.
- Researchers propose a new method to coax AlphaFold2 into modeling alternative protein shapes by manipulating multiple sequence alignments, suggesting that these alignments can reflect protein diversity.
- This innovative approach enhances AlphaFold2's utility by enabling the exploration of multiple protein conformations, which can be essential for various applications, including drug design and studying membrane proteins.
Article Abstract
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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436118 | PMC |
| http://dx.doi.org/10.1371/journal.pcbi.1010483 | DOI Listing |
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