Martini-3 Coarse-Grained Models for the Bacterial Lipopolysaccharide Outer Membrane of Escherichia coli.

Abstract

The outer lipopolysaccharide (LPS) membrane of Gram-negative bacteria forms the main barrier for transport of antimicrobial molecules into the bacterial cell. In this study we develop coarse-grained models for the outer membrane of Escherichia coli in the Martini-3 framework. The coarse-grained model force field was parametrized and validated using all-atom simulations of symmetric membranes of lipid A and rough LPS as well as a complete asymmetric membrane of LPS with the O-antigen. The bonded parameters were obtained using an iterative refinement procedure with target bonded distributions obtained from all-atom simulations. The membrane thickness, area of the LPS, and density distributions for the different regions as well as the water and ion densities in Martini-3 simulations show excellent agreement with the all-atom data. Additionally the solvent accessible surface area for individual molecules in water was found to be in good agreement. The binding of calcium ions with phosphate and carboxylate moieties of LPS is accurately captured in the Martini-3 model, indicative of the integrity of the highly negatively charged LPS molecules in the outer membranes of Gram-negative bacteria. The melting transition of the coarse-grained lipid A membrane model was found to occur between 300 and 310 K, and the model captured variations in area per LPS, order parameter, and membrane thickness across the melting transition. Our study reveals that the proposed Martini-3 models for LPS are able to capture the physicochemical balance of the complex sugar architecture of the outer membrane of Escherichia coli. The coarse-grained models developed in this study would be useful for determining membrane protein interactions and permeation of potential antimicrobials through bacterial membranes at mesoscopic spatial and temporal scales.