Understanding epistatic networks in the B1 β-lactamases through coevolutionary statistical modeling and deep mutational scanning.

ABSTRACT: Throughout evolution, protein families undergo substantial sequence divergence while preserving structure and function. Although most mutations are deleterious, evolution can explore sequence space via epistatic networks of intramolecular interactions that alleviate the harmful mutations. However, comprehensive analysis of such epistatic networks across protein families remains limited. Thus, we conduct a family wide analysis of the B1 metallo-β-lactamases, combining experiments (deep mutational scanning, DMS) on two distant homologs (NDM-1 and VIM-2) and computational analyses (in silico DMS based on Direct Coupling Analysis, DCA) of 100 homologs. The methods jointly reveal and quantify prevalent epistasis, as ~1/3rd of equivalent mutations are epistatic in DMS. From DCA, half of the posi

SUBMITTER: Chen JZ 

PROVIDER: S-EPMC11442494 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature