Referenced in: none

Automatically associated channels: Slo1

Title: Molecular simulations reveal the mechanism and the determinants for ampicillin translocation through OmpF.

Authors: Amit Kumar, Eric Hajjar, Paolo Ruggerone, Matteo Ceccarelli

Journal, date & volume: J Phys Chem B, 2010 Jul 29 , 114, 9608-16

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20590090

Abstract
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.