Converging PMF calculations of antibiotic permeation across an outer membrane porin with sub-kilocalorie per mole accuracy

Abstract

AbstractThe emergence of multi-drug resistant pathogens led to a critical need for new antibiotics. A key property of effective antibiotics against Gram-negative bacteria is their ability to permeate through the bacterial outer membrane via transmembrane porin proteins. Molecular dynamics (MD) simulations are in principle capable of modeling antibiotic permeation across outer membrane porins (OMPs). However, owing to sampling problems, it has remained challenging to obtain converged potentials of mean force (PMFs) for antibiotic permeation across OMPs. Here, we investigated the convergence of PMFs obtained with three advanced flavors of the umbrella sampling (US) technique aimed to quantify the permeation of the antibiotic fosmidomycin across the OprO porin: (i) Hamiltonian replica-exchange with solute tempering in combination with US, (ii) simulated tempering-enhanced US, and (iii) replica-exchange US. To quantify the PMF convergence and to reveal hysteresis problems, we computed several independent sets of US simulations started from pulling simulations in outward and inward permeation directions. We find that replica-exchange US in combination with well-chosen restraints is highly successful for obtaining converged PMFs of fosmidomycin permeation through OprO, reaching PMFs converged to sub-kilocalorie per mole accuracy.TOC Graphic