Progress in Molecular Dynamics Simulations of Gram-Negative Bacterial Cell Envelopes

Abstract

Bacteria are protected by complex molecular architectures known as the cell envelope. The cell envelope is composed of regions with distinct chemical compositions and physical properties; namely membranes and a cell wall. To develop novel antibiotics to combat pathogenic bacteria, molecular level knowledge of the structure, dynamics and interplay between the chemical components of the cell envelope that surrounds bacterial cells is imperative. In addition, conserved molecular patterns associated with the bacterial envelope are recognized by receptors as part of the mammalian defensive response to infection, and an improved understanding of bacteria-host interactions would facilitate the search for novel immunotherapeutics. This Perspective introduces an emerging area of computational biology; multiscale molecular dynamics simulations of chemically complex models of bacterial lipids and membranes. We discuss progress to date, and identify areas for future development that will enable the study of aspects of the membrane components that are as yet unexplored by computational methods.Bacteria are divided into two categories, Gramnegative and Gram positive, both of which include pathogens that are harmful to humans. Gram-negative bacteria have cell envelopes composed of two membranes, separated by a region known as the periplasm. The outer membrane (OM) is asymmetric in nature; the two leaflets differ in their compositions. The inner membrane contains a symmetric arrangement of phospholipids. In contrast, Gram-positive bacteria contain only one membrane, which is similar in composition to the inner membrane of Gram-negative bacteria. Both types of bacteria have a cell wall, which is composed of the biopolymer peptidoglycan. The combination of membrane plus cell wall gives rise to the characteristic semi-permeable properties of the cell envelope. To be effective, antibiotics must either cause bacterial cell death or inhibit cell growth. In both cases they must interact with the cell envelope, as they must either (i) disrupt the cell envelope, such that the cell contents leak out, or (ii) cross the cell envelope to gain access to the interior of the cell, where they may interfere with essential cellular process such as DNA replication and metabolism. The emergence of antimicrobial resistance is recognized as a major threat to human health. 1 It is thus imperative to have a detailed knowledge of the structure-dynamics-function relationships of the cell wall and membranes, in order to develop new antibiotics under reduced pressure of resistance. Furthermore, molecules derived from the cell membrane and wall are utilized by the mammalian innate immune system to mount a defensive response. 2 Over-amplification of such pathways can lead to sepsis, which remains the primary cause of death due to infection, highlighting the need for an improved understanding of the molecular mechanisms of immunostimulation. Due to the numerous molecular components involved, studying biological membranes in an in vivo condition rema...

Fosfomycin Permeation through the Outer Membrane Porin OmpF

“…To this end, it was assumed that the permeation across the asymmetric OM is comparable to or smaller than that across symmetric membranes because of the presence of lipopolysaccharides in the outer leaflet of the asymmetric bilayer. Especially on the computational side, quite some effort has been made recently to be able to describe asymmetric membranes in atomic detail and to study translocation of ions and substrates through proteins embedded therein (17,18,(65)(66)(67). As already mentioned in the introduction, for the development of new antimicrobial treatments, it is of prime importance to better understand the transport across the OM of Gram-negative bacteria (14)(15)(16).…”

“…In general, the transport of antibiotic molecules, especially across the OM of Gram-negative bacteria, has been identified as one of the key problems in antibiotics research (14)(15)(16). Recently, considerable effort-both experimentally as well as theoretically-has been put into this subject (see, for example, (17)(18)(19)(20)(21)(22)(23)(24)(25)), which is quite complex, partially because of the large diversity of channels and the so far often-incomplete knowledge of their structure and functional properties.…”

Lipopolysaccharide Simulations are Sensitive to Phosphate Charge and Ion Parameterization

“…LPS models have been parameterized for all major families of molecular dynamics (MD) force fields, [23][24][25][26][27][28] and outer membrane simulations with LPS are increasingly more common. [29][30][31][32][33] However, the performance of common ion force fields with these LPS models has rarely been evaluated, and inconsistencies exist between different parameterizations. The…”

Insights into the Polyhexamethylene Biguanide (PHMB) Mechanism of Action on Bacterial Membrane and DNA: A Molecular Dynamics Study

“…[42][43][44] Recent simulations have also membrane proteins and the LPS. [45][46][47] It has been shown that fully hydrated mixed lipid charged bilayers made of phosphatidylethanolamine (POPE) and phosphatidylglycerol (POPG) in the proportion 3:1 and counterions are stable and can serve as a suitable model of the inner bacterial membrane. 48 In the present study, bacterial membranes were built using the CHARMM-GUI online server 49 in two sizes: 1) To study PHMB polymer-bilayer systems, the bilayer consisted of 192 POPE and 64 POPG lipids (structures are provided in Figure S2) in each leaflet (total of 512 lipids), and 2) the bilayer for the PHMB dimer-bilayer system had 48 POPE and 16 POPG lipids in each leaflet (total of 128 lipids).…”