Stochastic Gating and Drug–Ribosome Interactions

Autor: Kevin Y. Sanbonmatsu, Andrea C. Vaiana
Rok vydání: 2009
Předmět:
Zdroj: Journal of Molecular Biology. 386:648-661
ISSN: 0022-2836
DOI: 10.1016/j.jmb.2008.12.035
Popis: Gentamicin is a potent antibiotic used in combination therapy for inhalation Anthrax disease. The drug is also often used in therapy for Methicillin-Resistant Staphylococcus Aureus (MRSA). Gentamicin works by flipping a conformational switch on the ribosome, disrupting the reading head (i.e. 16S ribosomal decoding bases 1492–1493) used for decoding the 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 used an aggregate sampling of 15-microseconds, when summed over all replicas, allowing us to explicitly calculate the free energy landscape, including a rigorous treatment of enthalpic and entropic effects. Here, we show that the decoding bases flip on a time scale 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 non-specific binding landscape near the binding site and reveals that, rather than a two-state bound/unbound scenario, drug dissociation entails a shuttling between many metastable local minima in the free energy landscape. Special care is dedicated to validation of the obtained results, both by direct comparison to experiment and by estimating simulation convergence.
Databáze: OpenAIRE
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