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Undersampling and the inference of coevolution in proteins

Yaakov Kleeorin, William P. Russ, Olivier Rivoire, Rama Ranganathan
doi: https://doi.org/10.1101/2021.04.22.441025
Yaakov Kleeorin
1Center for Physics of Evolving Systems, Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, IL 60637
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William P. Russ
2Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Olivier Rivoire
3Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, F-75005 Paris, France
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  • For correspondence: olivier.rivoire@college-de-france.fr ranganathanr@uchicago.edu
Rama Ranganathan
1Center for Physics of Evolving Systems, Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, IL 60637
4The Pritzker School for Molecular Engineering, University of Chicago, Chicago, IL 60637
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  • For correspondence: olivier.rivoire@college-de-france.fr ranganathanr@uchicago.edu
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Abstract

Protein structure, function, and evolution depend on local and collective epistatic interactions between amino acids. A powerful approach to defining these interactions is to construct models of couplings between amino acids that reproduce the empirical statistics (frequencies and correlations) observed in sequences comprising a protein family. The top couplings are then interpreted. Here, we show that as currently implemented, this inference is always biased, a problem that fundamentally arises from the distinct scales at which epistasis occurs in proteins in the context of limited sampling. We show that these issues explain the ability of current approaches to predict tertiary contacts between amino acids and the inability to obviously expose larger networks of functionally-relevant, collectively evolving residues called sectors. This work provides a necessary foundation for more deeply understanding and improving evolution-based models of proteins.

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-ND 4.0 International license.
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Posted April 23, 2021.
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Undersampling and the inference of coevolution in proteins
Yaakov Kleeorin, William P. Russ, Olivier Rivoire, Rama Ranganathan
bioRxiv 2021.04.22.441025; doi: https://doi.org/10.1101/2021.04.22.441025
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Undersampling and the inference of coevolution in proteins
Yaakov Kleeorin, William P. Russ, Olivier Rivoire, Rama Ranganathan
bioRxiv 2021.04.22.441025; doi: https://doi.org/10.1101/2021.04.22.441025

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