The role of negative selection in protein evolution revealed through the energetics of the native state ensemble

Proteins
Jordan HoffmannVincent J Hilser

Abstract

Knowing the determinants of conformational specificity is essential for understanding protein structure, stability, and fold evolution. To address this issue, a novel statistical measure of energetic compatibility between sequence and structure was developed using an experimentally validated model of the energetics of the native state ensemble. This approach successfully matched sequences from a diverse subset of the human proteome to their respective folds. Unexpectedly, significant energetic compatibility between ostensibly unrelated sequences and structures was also observed. Interrogation of these matches revealed a general framework for understanding the origins of conformational specificity within a proteome: specificity is a complex function of both the ability of a sequence to adopt folds other than the native, and ability of a fold to accommodate sequences other than the native. The regional variation in energetic compatibility indicates that the compatibility is dominated by incompatibility of sequence for alternative fold segments, suggesting that evolution of protein sequences has involved substantial negative selection, with certain segments serving as "gatekeepers" that presumably prevent alternative structures. B...Continue Reading

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Citations

May 17, 2005·Journal of Molecular Biology·Zhirong Liu, Hue Sun Chan
Jun 2, 2017·Biochemistry·Muralikrishna Lella, Radhakrishnan Mahalakshmi
Mar 11, 2018·Nature Communications·Alex J DeGraveLillian T Chong
Sep 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Min-Hyung ChoVincent J Hilser
Mar 28, 2021·Science Advances·Erwin PannecouckeSavvas N Savvides

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