The nature of sequence and structure divergence in the Haloalkanoate Dehalogenase SuperFamily (HADSF)

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).