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Current protein structure predictors do not produce meaningful folding pathways

View ORCID ProfileCarlos Outeiral, View ORCID ProfileDaniel A. Nissley, View ORCID ProfileCharlotte M. Deane
doi: https://doi.org/10.1101/2021.09.20.461137
Carlos Outeiral
1Department of Statistics, University of Oxford, 24-29 St Giles’, OX1 3PB, United Kingdom
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Daniel A. Nissley
1Department of Statistics, University of Oxford, 24-29 St Giles’, OX1 3PB, United Kingdom
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Charlotte M. Deane
1Department of Statistics, University of Oxford, 24-29 St Giles’, OX1 3PB, United Kingdom
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  • For correspondence: deane@stats.ox.ac.uk
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ABSTRACT

Protein structure prediction has long been considered a gateway problem for understanding protein folding. Recent advances in deep learning have achieved unprecedented success at predicting a protein’s crystal structure, but whether this achievement relates to a better modelling of the folding process remains an open question. In this work, we compare the pathways generated by state-of-the-art protein structure prediction methods to experimental folding data. The methods considered were AlphaFold 2, RoseTTAFold, trRosetta, RaptorX, DMPfold, EVfold, SAINT2 and Rosetta. We find evidence that their simulated dynamics capture some information about the folding pathwhay, but their predictive ability is worse than a trivial classifier using sequence-agnostic features like chain length. The folding trajectories produced are also uncorrelated with parameters such as intermediate structures and the folding rate constant. These results suggest that recent advances in protein structure prediction do not yet provide an enhanced understanding of the principles underpinning protein folding.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted September 20, 2021.
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Current protein structure predictors do not produce meaningful folding pathways
Carlos Outeiral, Daniel A. Nissley, Charlotte M. Deane
bioRxiv 2021.09.20.461137; doi: https://doi.org/10.1101/2021.09.20.461137
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Current protein structure predictors do not produce meaningful folding pathways
Carlos Outeiral, Daniel A. Nissley, Charlotte M. Deane
bioRxiv 2021.09.20.461137; doi: https://doi.org/10.1101/2021.09.20.461137

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