A Glycam-Based Force Field for Simulations of Lipopolysaccharide Membranes: Parametrization and Validation

Kirschner, Karl N.; Lins, Roberto D.; Maaß, Astrid; Soares, Thereza A.

doi:10.1021/ct300534j

Cited by 103 publications

(152 citation statements)

References 93 publications

(175 reference statements)

Supporting

Mentioning

136

Contrasting

Order By: Relevance

“…). 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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…A complete molecular model of the core LPS layer of Pseudomonas aeruginosa has been simulated. Sugar groups recognizable by MBL are exposed terminally in a near-planar and dense glycan layer (19). This core layer can be modified by less abundant O-antigen glycosylations, lipid rafts, and embedded proteins, introducing nonplanarity, but this may be compensated by the flexibility and polydispersity of MBL.…”

Section: Distinct Prm/masp Complexes Cooperate On a Mixed Ligand Surfmentioning

confidence: 99%

Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes

Degn

Kjær

Kidmose

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Defining mechanisms governing translation of molecular binding events into immune activation is central to understanding immune function. In the lectin pathway of complement, the pattern recognition molecules (PRMs) mannan-binding lectin (MBL) and ficolins complexed with the MBL-associated serine proteases (MASP)-1 and MASP-2 cleave C4 and C2 to generate C3 convertase. MASP-1 was recently found to be the exclusive activator of MASP-2 under physiological conditions, yet the predominant oligomeric forms of MBL carry only a single MASP homodimer. This prompted us to investigate whether activation of MASP-2 by MASP-1 occurs through PRM-driven juxtaposition on ligand surfaces. We demonstrate that intercomplex activation occurs between discrete PRM/MASP complexes. PRM ligand binding does not directly escort the transition of MASP from zymogen to active enzyme in the PRM/MASP complex; rather, clustering of PRM/MASP complexes directly causes activation. Our results support a clustering-based mechanism of activation, fundamentally different from the conformational model suggested for the classical pathway of complement.innate immunity | collectin | inflammation | homeostasis

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide Simulations are Sensitive to Phosphate Charge and Ion Parameterization

Rice

Rooney

Greenwood

et al. 2019

Preprint

View full text Add to dashboard Cite

The high proportion of lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria make it a highly effective barrier to small molecules, antibiotic drugs, and other antimicrobial agents. Given this vital role in protecting bacteria from potentially hostile environments, simulations of LPS bilayers and outer membrane systems represent a critical tool for understanding the mechanisms of bacterial resistance and the development of new antibiotic compounds that circumvent these defenses. The basis of these simulations are parameterizations of LPS, which have been developed for all major molecular dynamics force fields. However, these parameterizations differ in both the protonation state of LPS as well as how LPS membranes behave in the presence of various ion species. To address these discrepancies and understand the effects of phosphate charge on bilayer properties, simulations were performed for multiple distinct LPS chemotypes with different ion parameterizations in both protonated or deprotonated lipid A states. These simulations show that bilayer properties, such as the area per lipid and inter-lipid hydrogen bonding, are highly influenced by the choice of phosphate group charges, cation type, and ion parameterization, with protonated LPS and monovalent cations with modified nonbonded parameters providing the best match to experiments. Additionally, alchemical free energy simulations were performed to determine theoretical pK a values for LPS, and subsequently validated by 31 P solid-state NMR experiments. Results from these complementary computational and experimental studies demonstrate that the protonated state dominates at physiological pH, contrary to the deprotonated form modeled by many LPS force fields.In all, these results highlight the sensitivity of LPS simulations to phosphate charge and ion parameters, while offering recommendations for how existing models should be updated for consistency between force fields as well as to best match experiments.

show abstract

A Glycam-Based Force Field for Simulations of Lipopolysaccharide Membranes: Parametrization and Validation

Cited by 103 publications

References 93 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

Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes

Lipopolysaccharide Simulations are Sensitive to Phosphate Charge and Ion Parameterization

Contact Info

Product

Resources

About