Bacterial Outer Membranes and Interactions with Proteins

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The cytoplasm of gram-negative bacteria is surrounded by a membrane composed of two layers: the inner membrane (or periplast) and the outer membrane (OM). The OM separates the periplasm from the external environment and functions as a selective barrier that prevents the entry of toxic molecules such as antibiotics and bile salts into the bacteria. This selective barrier is crucial for survival of bacteria in diverse and hostile environments. This project seeks to acquire an in-depth and molecular-level understanding of how the bacterial OMs behave and work for various types of bacteria, how membrane proteins behave in the OM and interact with the OM, and how solute molecules, especially antibiotics, can enter through the OMs. This will be accomplished using start-of-the-art molecular modeling and simulations. This project will also form the basis for a general approach for molecular modeling and simulation of the OM that will be freely available through the CHARMM-GUI website (www.charmm-gui.org) so that researchers in various disciplines can investigate other important OMs and associated proteins. Both graduate and undergraduate students will be trained in the interdisciplinary discipline of computational biophysics. In particular, this project will raise the scientific literacy of the public through the publication of research results and workshop participation.The cell envelope surrounding a gram-negative bacteria's cytoplasm is composed of an inner membrane, the periplasm, and an outer membrane (OM). The OM is unique in terms of having beta-barrel membrane proteins and a highly asymmetric lipid bilayer containing phospholipids in its inner leaflet and lipopolysaccharide (LPS) in its outer leaflet. This project aims to provide an in-depth and unprecedented understanding of the structural and dynamics of the OMs from various bacteria, interactions between proteins and OMs, and their influences on antibiotic permeation by establishing reliable computational methods for all-atom modeling and simulation of various complex OMs of gram-negative bacteria and membrane proteins in various OMs. The research will found the basis for a general approach of LPS/OM molecular modeling and simulation. This project also seeks to foster synergistic scientific research and education on LPS molecules and bacterial OMs by providing reliable and general computational methods (through LPS Modeler and Outer Membrane Builder in CHARMM-GUI) to students and researchers in the simulation community and other disciplines.