Veterans Affairs Northeast Ohio Healthcare System, Research Service, Cleveland, United States; Case Western Reserve University, Department of Molecular Biology and Microbiology, Cleveland, United States
Maria F Mojica
Veterans Affairs Northeast Ohio Healthcare System, Research Service, Cleveland, United States; Case Western Reserve University, Department of Infectious Diseases, School of Medicine, Cleveland, United States
Pratul K Agarwal
Department of Physiological Sciences and High-Performance Computing Center, Oklahoma State University, Stillwater, United States
Catherine L Tooke
University of Bristol, School of Cellular and Molecular Medicine, Bristol, United Kingdom
University College London, Department of Chemistry, London, United Kingdom; University College London, Institute of Structural and Molecular Biology, London, United Kingdom; University of Geneva, Pharmaceutical Sciences, Geneva, Switzerland
James Spencer
University of Bristol, School of Cellular and Molecular Medicine, Bristol, United Kingdom
Robert A Bonomo
Veterans Affairs Northeast Ohio Healthcare System, Research Service, Cleveland, United States; Case Western Reserve University, Department of Molecular Biology and Microbiology, Cleveland, United States; Case Western Reserve University, Department of Infectious Diseases, School of Medicine, Cleveland, United States; Case Western Reserve University, Department of Biochemistry, Cleveland, United States; Case Western Reserve University, Department of Pharmacology, Cleveland, United States; Case Western Reserve University, Department of Proteomics and Bioinformatics, Cleveland, United States; CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, United States
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 allosteric behavior, providing a mechanism by which amino acid substitutions may affect the relationship between spectrum of activity, catalytic turnover, and potential allosteric behavior in this clinically important enzyme family. Simulations of the type presented here will help in identifying and analyzing such differences.
