Abstract
The problem of predicting a protein’s 3D structure from its primary amino acid sequence is a longstanding challenge in structural biology. Recently, approaches like alphafold have achieved remarkable performance on this task by combining deep learning techniques with coevolutionary data from multiple sequence alignments of related protein sequences. The use of coevolutionary information is critical to these models’ accuracy, and without it their predictive performance drops considerably. In living cells, however, the 3D structure of a protein is fully determined by its primary sequence and the biophysical laws that cause it to fold into a low-energy configuration. Thus, it should be possible to predict a protein’s structure from only its primary sequence by learning an approximate biophysical energy function. We provide evidence that alphafold has learned such an energy function, and uses coevolution data to solve the global search problem of finding a low-energy conformation. We demonstrate that alphafold’slearned energy function can be used to rank the quality of candidate protein structures with state-of-the-art accuracy, without using any coevolution data. Finally, we explore several applications of this energy function, including the prediction of protein structures without multiple sequence alignments.
- Received 17 June 2022
- Accepted 18 October 2022
DOI:https://doi.org/10.1103/PhysRevLett.129.238101
Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article’s title, journal citation, and DOI.
Published by the American Physical Society
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Machine-Learning Model Reveals Protein-Folding Physics
Published 28 November 2022
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