Abstract
Though the number of protein folds is predicted to be finite, the universe of protein structures is vast and diverse. Thus understanding evolution of protein folds is a fundamental research challenge. The HADSF serves as an ideal model as it has a modular architecture where the conserved, Rossmann fold core domain is accessorized by a variable cap domain. This work aims to determine the impact of the cap domain on the sequence and structure divergence of the core domain. By performing quantitative analysis on a dataset of core‐domain‐only and cap‐domain‐ only structures, we have uncovered some basic protein design principles. We find that the relationship between sequence and structure divergence is robust, non‐linear (ρ=0.69) and, independent of the corresponding cap type. Core domains with the same cap type share greater similarity (<Similarity>; = 0.76) at the sequence and structure level than core domains with different cap types (<Similarity>; = 0.64), consistent with coevolution of the cap and core domains. Moreover, this similarity between cores is a global phenomenon with contributions from all residues of the Rossmann fold. Together, these results are consistent with coevolution of the cap domain in the context of a thermodynamically stable core domain, a strategy that may be active in other multi‐domain families. This project was supported by National Institute of General Medical Sciences (U54GM093342).
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