What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

Khalid, Syma; Schroeder, Cyril; Bond, Peter J.; Duncan, Anna L.

doi:10.1099/mic.0.001165

Cited by 14 publications

(13 citation statements)

References 135 publications

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“…To build the coarse-grained systems of the subsection of SOI embedded in a membrane, the Martini Maker tool ( 87 ) from the CHARMM-GUI server ( 88 , 89 ) was used, whereas the whole SOI system (150 × 150 nm) was built with the insane tool ( 90 ). The Martini force fields have previously been shown to reproduce experimental LPS, OMP, and PL behaviors and are the industry standard coarse-grained models for bacterial membrane simulations ( 26 , 36 , 91 ). Three systems (OmpF + three OMPs, OMP island, and smaller OMP island) were embedded in an OM model composed of a 100% rough LPS (Lacking O-antigen) outer leaflet and an inner leaflet containing 90% 16:0 to 18:1 POPE, 5% 16:0 to 18:1 POPG, and 5% cardiolipin.…”

Section: Methodsmentioning

confidence: 99%

Lipids mediate supramolecular outer membrane protein assembly in bacteria

et al. 2022

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β Barrel outer membrane proteins (OMPs) cluster into supramolecular assemblies that give function to the outer membrane (OM) of Gram-negative bacteria. How such assemblies form is unknown. Here, through photoactivatable cross-linking into the Escherichia coli OM, coupled with simulations, and biochemical and biophysical analysis, we uncover the basis for OMP clustering in vivo. OMPs are typically surrounded by an annular shell of asymmetric lipids that mediate higher-order complexes with neighboring OMPs. OMP assemblies center on the abundant porins OmpF and OmpC, against which low-abundance monomeric β barrels, such as TonB-dependent transporters, are packed. Our study reveals OMP-lipid-OMP complexes to be the basic unit of supramolecular OMP assembly that, by extending across the entire cell surface, couples the requisite multifunctionality of the OM to its stability and impermeability.

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Section: Methodsmentioning

confidence: 99%

Lipids mediate supramolecular outer membrane protein assembly in bacteria

et al. 2022

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“…It seems likely, however, that this TEC's extended β-sheet structure would allow it a considerable degree of conformational flexibility that may allow it to accommodate a range of IM-OM center-to-center distances. In the future, it might be interesting to explore the potential flexibility of the Lpt TEC using MD simulations of the kind already used to study other TECs (nicely reviewed in Khalid et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Atomic Models of All Major Trans-Envelope Complexes Involved in Lipid Trafficking inEscherichia ColiConstructed Using a Combination of AlphaFold2, AF2Complex, and Membrane Morphing Simulations

McDonnell

Patel

Wehrspan

et al. 2023

Preprint

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In Gram-negative bacteria, several trans-envelope complexes (TECs) have been identified that span the periplasmic space in order to facilitate lipid transport between the inner- and outer-membranes. While partial or near-complete structures of some of these TECs have been solved by conventional experimental techniques, most remain incomplete. Here we describe how a combination of computational approaches, constrained by experimental data, can be used to build complete atomic models for four TECs implicated in lipid transport in Escherichia coli. We use the DeepMind protein structure prediction algorithm, AlphaFold2, and a variant of it designed to predict protein complexes, AF2Complex, to predict the oligomeric states of key components of TECs and their likely interfaces with other components. After obtaining initial models of the complete TECs by superimposing predicted structures of subcomplexes, we use the membrane orientation prediction algorithm OPM to predict the likely orientations of the inner- and outer-membrane components in each TEC. Since, in all cases, the predicted membrane orientations in these initial models are tilted relative to each other, we devise a novel molecular mechanics-based strategy that we call membrane morphing that adjusts each TEC model until the two membranes are properly aligned with each other and separated by a distance consistent with estimates of the periplasmic width in E. coli. The study highlights the potential power of combining computational methods, operating within limits set by both experimental data and by cell physiology, for producing useable atomic structures of very large protein complexes.

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“…General diffusion porins are one of the few types of proteins investigated thoroughly by many techniques, including X-ray crystallography, atomic force microscopy, computer modeling, and electrophysiology. , Using different techniques has led to an understanding of the intake and uptake of molecules from porins. X-ray crystallography resolves several porin structures; the internal loop 3 forms a constriction at about half the height of the β-barrel.…”

Section: Outer Membrane Proteins and Antibiotic Resistance In Salmonellamentioning

confidence: 99%

Outer Membrane Proteins and Efflux Pumps Mediated Multi-Drug Resistance in Salmonella: Rising Threat to Antimicrobial Therapy

Akshay,

Deekshit,

Mohan Raj

et al. 2023

ACS Infect. Dis.

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Despite colossal achievements in antibiotic therapy in recent decades, drug-resistant pathogens have remained a leading cause of death and economic loss globally. One such WHO-critical group pathogen is Salmonella. The extensive and inappropriate treatments for Salmonella infections have led from multi-drug resistance (MDR) to extensive drug resistance (XDR). The synergy between efflux-mediated systems and outer membrane proteins (OMPs) may favor MDR in Salmonella. Differential expression of the efflux system and OMPs (influx) and positional mutations are the factors that can be correlated to the development of drug resistance. Insights into the mechanism of influx and efflux of antibiotics can aid in developing a structurally stable molecule that can be proficient at escaping from the resistance loops in Salmonella. Understanding the strategic responsibilities and developing policies to address the surge of drug resistance at the national, regional, and global levels are the needs of the hour. In this Review, we attempt to aggregate all the available research findings and delineate the resistance mechanisms by dissecting the involvement of OMPs and efflux systems. Integrating major OMPs and the efflux system’s differential expression and positional mutation in Salmonella may provide insight into developing strategic therapies for one health application.

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What have molecular simulations contributed to understanding of Gram-negative bacterial cell envelopes?

Cited by 14 publications

References 135 publications

Lipids mediate supramolecular outer membrane protein assembly in bacteria

Lipids mediate supramolecular outer membrane protein assembly in bacteria

Atomic Models of All Major Trans-Envelope Complexes Involved in Lipid Trafficking inEscherichia ColiConstructed Using a Combination of AlphaFold2, AF2Complex, and Membrane Morphing Simulations

Outer Membrane Proteins and Efflux Pumps Mediated Multi-Drug Resistance in Salmonella: Rising Threat to Antimicrobial Therapy

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