How structural and physicochemical determinants shape sequence constraints in a functional enzyme.

ABSTRACT: The need for interfacing structural biology and biophysics to molecular evolution is being increasingly recognized. One part of the big problem is to understand how physics and chemistry shape the sequence space available to functional proteins, while satisfying the needs of biology. Here we present a quantitative, structure-based analysis of a high-resolution map describing the tolerance to all substitutions in all positions of a functional enzyme, namely a TEM lactamase previously studied through deep sequencing of mutants growing in competition experiments with selection against ampicillin. Substitutions are rarely observed within 7 Å of the active site, a stringency that is relaxed slowly and extends up to 15-20 Å, with buried residues being especially sensitive. Substitution patterns

SUBMITTER: Abriata LA 

PROVIDER: S-EPMC4338278 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature