Molecular Dynamics Simulations Reveal Mechanistic Details of Polymyxin Penetration into both Membranes of E. coli

Abstract

Gram-negative bacteria such as E.coli are protected by a surprisingly complex cell envelope. The cell envelope is composed of two membranes that form a protective barrier around the cells, and control the influx and efflux of solutes via various routes. Lysing the cell by disrupting the membranes, or permeating across them to gain access to the cell interior are key properties for antimicrobial agents. Polymyxins are a class of antibiotics that have been shown to be highly active against Gram-negative bacteria. It is thought they enter bacterial cells through a self-uptake mechanism, although the molecular details of the mechanism are still unclear.We present, to our knowledge, the first molecular dynamics simulation study of an antimicrobial peptide, with both membranes of E.coli. Our model of the outer membrane contains lipopolysaccharide molecules in the inner leaflet and a mixture of ohosphilipids in the inner leaflet. In contrast, the inner membrane is comprised only of phospholipids. Our simulations reveal the effects of Polymyxin B1 (PMB1) binding on the physical properties of each membrane. Thus they are able to identify potentially different mechanisms for membrane disruption by PMB1. Peptide aggregation and insertion of one peptide tail was observed in the outer membrane. In contrast, PMB1 peptides insert readily as monomers, accompanied by water penetration into the inner membrane. Our simulations demonstrate the importance of capturing relevant details of biological complexity, in molecular models of biological membrane systems.