Eccleston, RC; Pollock, DD; Goldstein, RA; (2021) Selection for cooperativity causes epistasis predominately between native contacts and enables epistasis-based structure reconstruction. Proceedings of the National Academy of Sciences of the United States of America , 118 (16) , Article e2010057118. 10.1073/pnas.2010057118.

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Abstract

We investigated the relationship between cooperativity and epistasis and found low cooperativity results in high epistasis between nonnative contacts, whereas high cooperatively results in epistasis mainly between native contacts. This provides a mechanistic explanation for why epistasis measurements can be used to reconstruct protein structure. The structure of GB1 protein has been successfully reconstructed using epistasis measurements, and we calculated its epistasis distribution for a cooperative and a noncooperative model. The structure of the native state is clearly mapped out in the cooperative model but becomes obscured in the noncooperative model due to the presence of a folding intermediate. We thus conclude that using epistasis measurements to reconstruct the native state of proteins with stable intermediates may not be appropriate.

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