Fast prediction of antibiotic permeability through membrane channels using Brownian dynamics

Abstract

The efficient permeation across the Gram-negative bacterial membrane is an important step in the overall process of antibacterial action of a molecule and the one that has posed a significant hurdle on the way toward approved antibiotics. Predicting the permeability for a large library of molecules and assessing the effect of different molecular transformations on permeation rates of a given molecule is critical to the development of effective antibiotics. We present a computational approach for obtaining estimates of molecular permeability through a porin channel in a matter of hours using a Brownian dynamics approach. The fast sampling using a temperature acceleration scheme enables the approximate estimation of permeability using the inhomogeneous solubility diffusion model. Although the method is a significant approximation to similar all-atom approaches tested previously, we show that the present approach predicts permeabilities that correlate fairly well with the respective experimental permeation rates from liposome swelling experiments and accumulation rates from antibiotic accumulation assays, and is significantly, i.e., about 14 times, faster compared with a previously reported approach. The possible applications of the scheme in high-throughput screening for fast permeators are discussed.