title: Molecular simulations reveal the mechanism and the determinants for ampicillin translocation through OmpF.
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.
authors.affiliation: Department of Physics, University of Cagliari and Istituto Officina dei Materiali/CNR UOS SLACS, I-09042 Monserrato (CA), Italy.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Eric
authors.initials: E
authors.lastname: Hajjar
authors.forename: Paolo
authors.initials: P
authors.lastname: Ruggerone
authors.forename: Matteo
authors.initials: M
authors.lastname: Ceccarelli
mesh_terms: D000667:Ampicillin / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D056004:Molecular Dynamics Simulation; D018272:Porins / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; C109237:OmpF protein; D018272:Porins; D000667:Ampicillin