Allosteric communication in class A β-lactamases occurs via cooperative coupling of loop dynamics.

ABSTRACT: Understanding allostery in enzymes and tools to identify it offer promising alternative strategies to inhibitor development. Through a combination of equilibrium and nonequilibrium molecular dynamics simulations, we identify allosteric effects and communication pathways in two prototypical class A β-lactamases, TEM-1 and KPC-2, which are important determinants of antibiotic resistance. The nonequilibrium simulations reveal pathways of communication operating over distances of 30 Å or more. Propagation of the signal occurs through cooperative coupling of loop dynamics. Notably, 50% or more of clinically relevant amino acid substitutions map onto the identified signal transduction pathways. This suggests that clinically important variation may affect, or be driven by, differences in alloster

SUBMITTER: Galdadas I 

PROVIDER: S-EPMC8060031 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature