Hydration, ionic valence and cross-linking propensities of cations determine the stability of lipopolysaccharide (LPS) membranes

Nascimento, Agrinaldo; Pontes, Frederico J. S.; Lins, Roberto D.; Soares, Thereza A.

doi:10.1039/c3cc46918b

Cited by 44 publications

(69 citation statements)

References 32 publications

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“…). It should also be noted that the polysaccharide region is highly hydrated and each counter‐ion is coordinated on average by four water molecules . an effect found by other researchers as well .…”

Section: Resultsmentioning

confidence: 56%

Modeling the electrostatic potential of asymmetric lipopolysaccharide membranes: The MEMPOT algorithm implemented in DelPhi

Dias

Soares

et al. 2014

J Comput Chem

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Four chemotypes of the Rough lipopolysaccharides (LPS) membrane from Pseudomonas aeruginosa were investigated by a combined approach of explicit water molecular dynamics (MD) simulations and Poisson-Boltzmann continuum electrostatics with the goal to deliver the distribution of the electrostatic potential across the membrane. For the purpose of this investigation, a new tool for modeling the electrostatic potential profile along the axis normal to the membrane, MEMPOT, was developed and implemented in DelPhi. Applying MEMPOT on the snapshots obtained by MD simulations, two observations were made: (a) the average electrostatic potential has a complex profile, but is mostly positive inside the membrane due to the presence of Ca2+ ions which overcompensate for the negative potential created by lipid phosphate groups; and (b) correct modeling of the electrostatic potential profile across the membrane requires taking into account the water phase, while neglecting it (vacuum calculations) results in dramatic changes including a reversal of the sign of the potential inside the membrane. Furthermore, using DelPhi to assign different dielectric constants for different regions of the LPS membranes, it was investigated whether a single frame structure before MD simulations with appropriate dielectric constants for the lipid tails, inner, and the external leaflet regions, can deliver the same average electrostatic potential distribution as obtained from the MD-generated ensemble of structures. Indeed, this can be attained by using smaller dielectric constant for the tail and inner leaflet regions (mostly hydrophobic) than for the external leaflet region (hydrophilic) and the optimal dielectric constant values are chemotype-specific.

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Section: Resultsmentioning

confidence: 56%

Modeling the electrostatic potential of asymmetric lipopolysaccharide membranes: The MEMPOT algorithm implemented in DelPhi

Dias

Soares

et al. 2014

J Comput Chem

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“…Also, LPS changes the hydration profile at membrane–water interfaces. 43 The packing and rigidity of LPS bilayers are expected to affect permeation of amphiphilic and hydrophobic antibiotics. However, this picture remains incomplete because about 50% of the E. coli OM mass consists of protein and the OM resembles a LPS–protein aggregate.…”

Section: The Two-membrane Barrier Of Gram-negative Bacteriamentioning

confidence: 99%

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

2015

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Gram-negative bacteria are intrinsically resistant to many antibiotics. Species that have acquired multidrug resistance and cause infections that are effectively untreatable present a serious threat to public health. The problem is broadly recognized and tackled at both the fundamental and applied levels. This paper summarizes current advances in understanding the molecular bases of the low permeability barrier of Gram-negative pathogens, which is the major obstacle in discovery and development of antibiotics effective against such pathogens. Gaps in knowledge and specific strategies to break this barrier and to achieve potent activities against difficult Gram-negative bacteria are also discussed.

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“…(For more recent progress, see Refs. [12][13][14][15][16].) Indeed, increased OM permeability is correlated with enhanced susceptibility of Gram-negative bacteria to AMPs and antibiotics [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…A better understanding of how AMPs reduce OM permeability will benefit our effort for combating these bacteria. Indeed, several attempts have recently been made to advance our understanding of OM permeability [12][13][14][15][16]. For instance, an in vitro model of the Escherichia coli cell surface has been proposed and used in further unravelling the effects of divalent cations on OM permeability [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides

et al. 2017

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The permeability of the bacterial outer membrane, enclosing Gram-negative bacteria, depends on the interactions of the outer, lipopolysaccharide (LPS) layer, with surrounding ions and molecules. We present a coarse-grained model for describing how cationic amphiphilic molecules (e.g., antimicrobial peptides) interact with and perturb the LPS layer in a biologically relevant medium, containing monovalent and divalent salt ions (e.g., Mg 2+ ). In our approach, peptide binding is driven by electrostatic and hydrophobic interactions and is assumed to expand the LPS layer, eventually priming it for disruption. Our results suggest that in parameter ranges of biological relevance (e.g., at micromolar concentrations) the antimicrobial peptide magainin 2 effectively disrupts the LPS layer, even though it has to compete with Mg 2+ for the layer. They also show how the integrity of LPS is restored with an increasing concentration of Mg 2+ . Using the approach, we make a number of predictions relevant for optimizing peptide parameters against Gram-negative bacteria and for understanding bacterial strategies to develop resistance against cationic peptides.

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Hydration, ionic valence and cross-linking propensities of cations determine the stability of lipopolysaccharide (LPS) membranes

Cited by 44 publications

References 32 publications

Modeling the electrostatic potential of asymmetric lipopolysaccharide membranes: The MEMPOT algorithm implemented in DelPhi

Modeling the electrostatic potential of asymmetric lipopolysaccharide membranes: The MEMPOT algorithm implemented in DelPhi

Permeability Barrier of Gram-Negative Cell Envelopes and Approaches To Bypass It

Opposing effects of cationic antimicrobial peptides and divalent cations on bacterial lipopolysaccharides

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