Identifying the Pathways to Permeation through OccD1 in the Outer Membranes of P. Aeruginosa

Abstract

Pseudomanas aeruginosa (PA) is a pathogenic Gram-negative bacterium that causes infections, which can often be fatal in hosts with compromised defence mechanisms. PA is difficult to combat due to its resistance to antibiotics. This resistance arises as a consequence of a number of factors including the presence of multidrug efflux pumps and the low permeability of the outer membrane. When designing drugs that target PA, it is imperative to consider how they will gain entry into the cell. Specific beta-barrel proteins control movement of large solutes through the outer membrane; due to the substrate-specific nature of these proteins, drug selection and design is not a straightforward process.We have performed modelling, docking and simulations to gain some insights into the origins of the substrate-specificity and the pathways of permeation through the OccD1 protein found in the outer membranes of PA. A combination of computational and experimental data allows us to predict the molecular interactions that lead to the preferential recognition of arginine and then to demonstrate how this can be modified by designing a mutant protein that preferentially binds glutamate. Extended simulations enable us to identify additional potential binding sites along the barrel, allowing us to build up a picture of the pathway taken by arginine to permeate through OccD1.