Abstract
Gentamicin is a potent antibiotic often used in therapy for methicillin-resistant Staphylococcusaureus. Gentamicin works by flipping a conformational switch on the ribosome, disrupting the reading head (i.e., 16S ribosomal decoding bases A1492-A1493 used for decoding messenger RNA. We use explicit solvent all-atom molecular simulation to study the thermodynamics of the ribosomal decoding site and its interaction with gentamicin. The replica exchange molecular dynamics simulations allow enhanced sampling of the unbinding free-energy landscape, including a rigorous treatment of enthalpic and entropic effects. The decoding bases flip on a timescale faster than that of gentamicin binding, supporting a stochastic gating mechanism for antibiotic binding, rather than an induced-fit model where the bases only flip in the presence of a ligand. The study also allows us to explore the nonspecific binding landscape near the binding site and reveals that, rather than a two-state bound/unbound scenario, drug dissociation entails shuttling between many metastable local minima in the free-energy landscape. Additional simulations address the effect of mutation/modification of the A-site on the free energy landscapes. In particular, mutations of base A1408 known to confer high-level resistance in “superbug” bacteria to common antibiotic therapies are investigated. Special care is dedicated to validation of the obtained results, both by direct comparison to experiment and by estimation of simulation convergence.
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