Covalent docking and molecular dynamics simulations reveal the specificity-shifting mutations Ala237Arg and Ala237Lys in TEM beta-lactamase.

ABSTRACT: The rate of modern drug discovery using experimental screening methods still lags behind the rate at which pathogens mutate, underscoring the need for fast and accurate predictive simulations of protein evolution. Multidrug-resistant bacteria evade our defenses by expressing a series of proteins, the most famous of which is the 29-kilodalton enzyme, TEM β-lactamase. Considering these challenges, we applied a covalent docking heuristic to measure the effects of all possible alanine 237 substitutions in TEM due to this codon's importance for catalysis and effects on the binding affinities of commercially-available β-lactam compounds. In addition to the usual mutations that reduce substrate binding due to steric hindrance, we identified two distinctive specificity-shifting TEM mutations, Ala2

SUBMITTER: Silva GMD 

PROVIDER: S-EPMC9269908 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature