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 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.
Highlights
The rise in antimicrobial resistance (AMR) is a growing global public health crisis (Centers for Disease Control and Prevention (U.S.), 2019)
To explore the conformational space of TEM-1 and KPC-2 in the ApoEQ and IBEQ states, we started by running a set of equilibrium simulations (20 replicas of 250 ns each) that resulted in 5 ms of accumulated simulation time per system
The low root mean-square deviation (RMSD) values are consistent with previously published results, which have shown class A b-lactamase enzymes to be largely rigid and conformationally stable when studied on long timescales and rarely divergent from the initial structure (Gobeil et al, 2019; Galdadas et al, 2018)
Summary
The rise in antimicrobial resistance (AMR) is a growing global public health crisis (Centers for Disease Control and Prevention (U.S.), 2019). The problem of AMR is urgent given the alarming proliferation of antibiotic resistance in bacteria; pathogens associated with both community-acquired and healthcare-associated infections are increasingly resistant to first-line and even reserve agents (Lythell et al, 2020). This poses a serious challenge obstacle in fighting common and severe bacterial infections, and reduces the viability and increases the risks of interventions such as orthopedic surgery and threatens new antibiotics coming to the market (Bush and Page, 2017). These enzymes hydrolyze the amide bond in the b-lactam ring, resulting in a product that is incapable of inhibiting PBPs (Palzkill, 2018)
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