Journal
JOURNAL OF PHYSICAL CHEMISTRY B
Volume 114, Issue 29, Pages 9608-9616Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jp9110579
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Funding
- EU [MRTN-CT-2005-019335]
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We use a multiscale approach, combining molecular dynamics simulations with metadynamics, to simulate the translocation of ampicillin through OmpF from Escherichia coli (E. coli). In-depth analysis has allowed us to reveal the complete picture of the translocation process in terms of both energetics and physicochemical properties. We have demonstrated the existence of a unique affinity site at the constriction region, accessible from both sides and defined by specific pore-antibiotic interactions. By providing optimal binding, the constriction region works like an enzyme toward the permeation of ampicillin. We find reduction in entropy to be compensated by enthalpic contributions from a favorable network of interactions (hydrogen bonds and hydrophobic contacts) which is also mediated by two slow water molecules bridging the antibiotic pore interactions. Finally, as ampicillin assumes a preferential value for a torsional angle when at the constriction region, we investigated the consequence of the conformational preorganization of ampicillin toward its translocation. As a whole, our analysis opens the way to chemical modifications of antibiotics to allow improving uptake through porins contributing to combat bacterial resistance.
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