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

2017 ◽  
Vol 8 (11) ◽  
pp. 2513-2518 ◽  
Author(s):  
Alister Boags ◽  
Pin-Chia Hsu ◽  
Firdaus Samsudin ◽  
Peter J. Bond ◽  
Syma Khalid
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Bacterial Cell ◽  
Gram Negative ◽  
Dynamics Simulations ◽  
Cell Envelopes

The membranes of Gram-negative bacteria: progress in molecular modelling and simulation

2015 ◽  
Vol 43 (2) ◽  
pp. 162-167 ◽  
Author(s):  
Syma Khalid ◽  
Nils A. Berglund ◽  
Daniel A. Holdbrook ◽  
Yuk M. Leung ◽  
Jamie Parkin
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Bilayers ◽  
Molecular Modelling ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Bacterial Membranes ◽  
Lipid Species ◽  
Membrane Models ◽  
Dynamics Simulations

Molecular modelling and simulations have been employed to study the membranes of Gram-negative bacteria for over 20 years. Proteins native to these membranes, as well as antimicrobial peptides and drug molecules have been studied using molecular dynamics simulations in simple models of membranes, usually only comprising one lipid species. Thus, traditionally, the simulations have reflected the majority of in vitro membrane experimental setups, enabling observations from the latter to be rationalized at the molecular level. In the last few years, the sophistication and complexity of membrane models have improved considerably, such that the heterogeneity of the lipid and protein composition of the membranes can now be considered both at the atomistic and coarse-grain levels of granularity. Importantly this means relevant biology is now being retained in the models, thereby linking the in silico and in vivo scenarios. We discuss recent progress in simulations of proteins in simple lipid bilayers, more complex membrane models and finally describe some efforts to overcome timescale limitations of atomistic molecular dynamics simulations of bacterial membranes.

scholarly journals Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Runrun Wu ◽  
Jeremy W. Bakelar ◽  
Karl Lundquist ◽  
Zijian Zhang ◽  
Katie M. Kuo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Single Unit ◽  
Outer Membrane Proteins ◽  
Conformational Dynamics ◽  
Accessory Proteins ◽  
Gram Negative Bacteria ◽  
Folding Intermediate ◽  
Gram Negative ◽  
Dynamics Simulations

AbstractIn Gram-negative bacteria, the biogenesis of β-barrel outer membrane proteins is mediated by the β-barrel assembly machinery (BAM). The mechanism employed by BAM is complex and so far- incompletely understood. Here, we report the structures of BAM in nanodiscs, prepared using polar lipids and native membranes, where we observe an outward-open state. Mutations in the barrel domain of BamA reveal that plasticity in BAM is essential, particularly along the lateral seam of the barrel domain, which is further supported by molecular dynamics simulations that show conformational dynamics in BAM are modulated by the accessory proteins. We also report the structure of BAM in complex with EspP, which reveals an early folding intermediate where EspP threads from the underside of BAM and incorporates into the barrel domain of BamA, supporting a hybrid-barrel budding mechanism in which the substrate is folded into the membrane sequentially rather than as a single unit.

scholarly journals Interactions of surfactants with the bacterial cell wall and inner membrane: Revealing the link between aggregation and antimicrobial activity

2021 ◽  
Author(s):  
Pradyumn Sharma ◽  
Rakesh K. Vaiwala ◽  
Srividhya Parthasarathi ◽  
Nivedita Patil ◽  
Morris Waskar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cell Wall ◽  
Molecular Dynamics Simulations ◽  
Bacterial Cell ◽  
Cell Envelope ◽  
Bacterial Cell Wall ◽  
Inner Membrane ◽  
Bending Modulus ◽  
Dynamics Simulations ◽  
Peptidoglycan Layer

Surfactants with their intrinsic ability to solubilize lipids are widely used as antibacterial agents. Interaction of surfactants with the bacterial cell envelope is complicated due to their propensity to aggregate. It is important to discern the interactions of micellar aggregates and single surfactants on the various components of the cell envelope to improve selectivity and augment the efficacy of surfactant-based products. In this study, we present a combined experimental and molecular dynamics investigation to unravel the molecular basis for the superior kill efficacy of laurate over oleate observed in contact time assays with live E. coli. To gain a molecular understanding of these differences, we performed all-atom molecular dynamics simulations to observe the interactions of surfactants with the periplasmic peptidoglycan layer and the inner membrane of Gram-negative bacteria. The peptidoglycan layer allows a greater number of translocation events for laurate when compared with oleate molecules. More interestingly, aggregates did not translocate the peptidoglycan layer, thereby revealing an intrinsic sieving property of the bacterial cell wall to effectively modulate the surfactant concentration at the inner membrane. The molecular dynamics simulations exhibit greater thinning of the inner membrane in the presence of laurate when compared with oleate, and laurate induced greater disorder and decreased the bending modulus of the inner membrane to a greater extent. The enhanced antimicrobial efficacy of laurate over oleate was further verified by experiments with giant unilamellar vesicles, which revealed that laurate induced vesicle rupture at lower concentrations in contrast to oleate. The novel molecular insights gained from our study uncovers hitherto unexplored pathways to rationalize the development of antimicrobial formulations and therapeutics.

scholarly journals Glucose transport via the pseudomonad porin OprB: implications for the design of Trojan Horse anti-infectives

2019 ◽  
Vol 21 (16) ◽  
pp. 8457-8463 ◽  
Author(s):  
Joan Coines ◽  
Silvia Acosta-Gutierrez ◽  
Igor Bodrenko ◽  
Carme Rovira ◽  
Matteo Ceccarelli
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Glucose Transport ◽  
Trojan Horse ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dynamical Features ◽  
Dynamics Simulations

Knowing the structural and dynamical features of specific porins from poor-permeable Gram-negative bacteria helps to design anti-infectives with optimal permeation. Molecular dynamics simulations can characterize and quantify the transport of substrates through these specific porins.

scholarly journals Molecular dynamics simulations informed by membrane lipidomics reveal the structure–interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii

2020 ◽  
Vol 75 (12) ◽  
pp. 3534-3543 ◽  
Author(s):  
Xukai Jiang ◽  
Kai Yang ◽  
Bing Yuan ◽  
Meiling Han ◽  
Yan Zhu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Acinetobacter Baumannii ◽  
Outer Membrane ◽  
Electrostatic Interactions ◽  
Lipid A ◽  
Gram Negative ◽  
Structure Interaction ◽  
Dynamics Simulations ◽  
Interaction Relationship

Abstract Background MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative ‘superbugs’, including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. Methods We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure–interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. Results Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. Conclusions The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure–interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.

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