scholarly journals Molecular dynamics simulations of bacterial outer membrane lipid extraction: Adequate sampling?

2020 ◽  
Vol 153 (4) ◽  
pp. 044122
Author(s):  
Jonathan Shearer ◽  
Jan K. Marzinek ◽  
Peter J. Bond ◽  
Syma Khalid
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Outer Membrane ◽  
Lipid Extraction ◽  
Membrane Lipid ◽  
Adequate Sampling ◽  
Bacterial Outer Membrane ◽  
Dynamics Simulations

scholarly journals Molecular Dynamics Simulations of Bacterial Outer Membrane Lipid Extraction: Adequate Sampling?

2020 ◽  
Author(s):  
Jonathan Shearer ◽  
Jan K. Marzinek ◽  
Peter J. Bond ◽  
Syma Khalid
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Outer Membrane ◽  
Lipid Extraction ◽  
Membrane Lipid ◽  
Computational Effort ◽  
Potential Of Mean Force ◽  
Coarse Grained ◽  
Adequate Sampling ◽  
Dynamics Simulations

AbstractThe outer membrane of Gram-negative bacteria is almost exclusively composed of lipopolysaccharide in its outer leaflet, whereas the inner leaflet contains a mixture of phospholipids. Lipopolysaccharide diffuses at least an order of magnitude slower than phospholipids, which can cause issues for molecular dynamics simulations in terms of adequate sampling. Here we test a number of simulation protocols for their ability to achieve convergence with reasonable computational effort using the MARTINI coarse-grained force-field. This is tested in the context both of potential of mean force (PMF) calculations for lipid extraction from membranes, and of lateral mixing within the membrane phase. We find that decoupling the cations that cross-link the lipopolysaccharide headgroups from the extracted lipid during PMF calculations is the best approach to achieve convergence comparable to that for phospholipid extraction. We also show that lateral lipopolysaccharide mixing/sorting is very slow and not readily addressable even with Hamiltonian replica exchange. We discuss why more sorting may be unrealistic for the short (microseconds) timescales we simulate and provide an outlook for future studies of lipopolysaccharide-containing membranes.

Molecular dynamics simulations of outer-membrane protease T fromE. colibased on a hybrid coarse-grained/atomistic potential

2006 ◽  
Vol 18 (14) ◽  
pp. S347-S355 ◽  
Author(s):  
Marilisa Neri ◽  
Claudio Anselmi ◽  
Vincenzo Carnevale ◽  
Attilio V Vargiu ◽  
Paolo Carloni
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Outer Membrane ◽  
Coarse Grained ◽  
Dynamics Simulations

scholarly journals The Lazy Life of Lipid-Linked Oligosaccharides in All Life Domains

2019 ◽  
Author(s):  
Pablo Ricardo Arantes ◽  
Conrado Pedebos ◽  
Marcelo D. Poleto ◽  
Laércio Pol-Fachin ◽  
Hugo Verli
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Membrane Lipid ◽  
Membrane Dynamics ◽  
En Bloc ◽  
Future Studies ◽  
Head Groups ◽  
Domains Of Life ◽  
Glycosylation Pathway ◽  
Dynamics Simulations

<div> <div> <div> <p>Lipid-linked oligosaccharides (LLOs) plays an important role in the N-glycosylation pathway as the donor substrate of oligosaccharyltransferases (OSTs), which are respon- sible for the en bloc transfer of glycan chains onto a nascent polypeptide. The lipid component of LLO in both eukarya and archaea consists of a dolichol, and an unde- caprenol in prokarya, whereas the number of isoprene units may change between species. Given the potential relevance of LLOs and their related enzymes to diverse biotechno- logical applications, obtaining reliable LLO models from distinct domains of life could support further studies on complex formation and their processing by OSTs, as well as protein engineering on such systems. In this work, molecular modeling, such as quantum mechanics calculations, molecular dynamics simulations, and metadynamics were employed to study eukaryotic (Glc3-Man9-GlcNAc2-PP-Dolichol), bacterial (Glc1- GalNAc5-Bac1-PP-Undecaprenol) and archaeal (Glc1-Man1-Gal1-Man1-Glc1-Gal1-Glc1- P-Dolichol) LLO in membrane bilayers. Microsecond molecular dynamics simulations and metadynamics calculations of LLOs revealed that glycan chains are more prone to interact with the membrane lipid head groups, while the PP linkages are positioned at the lipid phosphate head groups level. Dynamics of isoprenoid chains embedded within the bilayer are described and membrane dynamics and its related properties are also investigated. Overall, there are similarities regarding the structural and dynamics of the eukaryotic, the bacterial and the archaeal LLOs in bilayers, which can support the comprehension of their association with OSTs. This data may support future studies on the transferring mechanism of the oligosaccharide chain to an acceptor protein. </p> </div> </div> </div>

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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