Influence of Yersinia Pestis Lipopolysaccharide Structure upon Outer Membrane Dynamics: Insight from Molecular Dynamics Simulations

Abstract

Yersinia pestis, the causative agent of plague, is not only still prevalent in many different parts of the world but is also classified as a potential biological warfare agent. Y. pestis is a Gram-negative bacterium and is therefore surrounded by two membranes. The outer of these two membranes is arranged with an asymmetric lipid distribution; phospholipids comprise the inner leaflet of the membrane, while the outer leaflet contains the complex glycolipid lipopolysaccharide (LPS). Not only is this outer membrane important in functioning as the first barrier that molecules must cross to enter the bacterial cell but also because it is a potential target for antimicrobial drugs. The LPS within the outer membrane of Y. pestis is unusual in the fact that it undergoes substantial, temperature-dependent, structural variation. This temperature dependence of the LPS structure is important in both resistance to antimicrobial peptides and the ability to evade the human innate immune system.In this presented work, we aimed to explore the details of the molecular interactions which govern the properties of the outer membrane of Y. pestis. In particular, atomistic models for the different temperature-dependent structural variations of the LPS have been constructed. Subsequent molecular dynamics simulations have elucidated the impact of these structural changes upon the properties of the outer membrane. Finally the impact of the addition of a cationic monosaccharide to lipid A, a common structural variant that increases the resistance of Y. pestis to cationic antimicrobial peptides, has also been explored through molecular simulation.