Living on the edge: Simulations of bacterial outer-membrane proteins

Pavlova, Ànna; Hwang, Hyea; Lundquist, Karl; Balusek, Curtis; Gumbart, James C.

doi:10.1016/j.bbamem.2016.01.020

Cited by 40 publications

(33 citation statements)

References 87 publications

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“…Examples include: (a) the use of MD simulations to understand the stabilization of proteins by glycosylation, 8–10 (b) insightful attempts to model and simulate the peptidoglycan layers of Gram-positive 11 and Gram-negative 12 bacteria, and (c) the use of MD to simulate lipid-linked lipopolysaccharides, 13–14 whose carbohydrate chains are known to interact with outer membrane proteins. 15 …”

mentioning

confidence: 99%

Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

Lay

Miller

Elcock

2017

J. Chem. Theory Comput.

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AMBER/GLYCAM and CHARMM are popular force fields for simulations of amino acids and sugars. Here we report excessively attractive amino acid-sugar interactions in both force fields, and corrections to nonbonded interactions that match experimental osmotic pressures of mixed aqueous solutions of diglycine and sucrose. The modified parameters also improve the ΔGtrans of diglycine from water to aqueous sucrose and, with AMBERff99SB/GLYCAM06, eliminate a caging effect seen in previous simulations of the protein ubiquitin with glucose.

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mentioning

confidence: 99%

Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

Lay

Miller

Elcock

2017

J. Chem. Theory Comput.

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“…Up until recently, it was poorly understood, which prevented even in silico approaches. Our work has been enabled by recent breakthroughs in atomistic simulations, which now permit explicit modeling of realistic outer membranes 20,[22][23][24][25] .…”

Section: Articlementioning

confidence: 99%

Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface

et al. 2020

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Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, although the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood. Here we report, immunization with the trimeric porin OmpD from Salmonella Typhimurium (STmOmpD) protects against infection. Atomistic molecular dynamics simulations indicate this is because OmpD trimers generate footprints within the O-Ag layer sufficiently sized for a single IgG Fab to access. While STmOmpD differs from its orthologue in S. Enteritidis (SEn) by a single amino-acid residue, immunization with STmOmpD confers minimal protection to SEn. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization. Thus, both the chemical and physical structure of O-Ag are key for the presentation of specific epitopes within proteinaceous surface-antigens. This enhances combinatorial antigenic diversity in Gram-negative bacteria, while reducing associated fitness costs.

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“…28-31 However, MD simulations have not been used to study the stability of GPCRs embedded in detergent micelles. The receptor we have used for this study, the human adenosine A 2A receptor (A 2A R), was chosen because its stability in lipid bilayers has already been thoroughly studied by MD simulations, both for the wild type receptor and engineered thermostable mutant in different conformations.…”

Section: Introductionmentioning

confidence: 99%

How Do Short Chain Nonionic Detergents Destabilize G-Protein-Coupled Receptors?

et al. 2016

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Stability of detergent-solubilized GPCRs is crucial for their purification in a biologically relevant state and it is well-known that short chain detergents such as octylglucoside are more denaturing than long chain detergents such as dodecylmaltoside. However, the molecular basis for this phenomenon is poorly understood. To gain insights into the mechanism of detergent destabilization of GPCRs, we used atomistic molecular dynamics simulations of thermostabilized adenosine receptor (A2AR) mutants embedded in either a lipid bilayer or detergent micelles of alkylmaltosides and alkyl-glucosides. A2AR mutants in dodecylmaltoside or phospholipid showed low flexibility and good interhelical packing. In contrast, A2AR mutants in either octylglucoside or nonylglucoside showed decreased α-helicity in transmembrane regions, decreased α-helical packing and the interpenetration of detergent molecules between transmembrane α-helices. This was not observed in octylglucoside containing phospholipid. Cholesteryl hemisuccinate in dodecylmaltoside increased the energetic stability of the receptor by wedging into crevices on the hydrophobic surface of A2AR, increasing packing interactions within the receptor and stiffening the detergent micelle. The data suggest a three-stage process for the initial events in the destabilization of GPCRs by octylglucoside: (i) highly mobile detergent molecules form small micelles around the receptor; (ii) loss of α-helicity and decreased interhelical packing interactions in transmembrane regions through increased receptor thermal motion; (iii) transient separation of transmembrane helices allowed penetration of detergent molecules into the core of the receptor. The relative hydration of the headgroup and alkyl chain correlates with detergent harshness and suggests new avenues to develop milder versions of octylglucoside for receptor crystallization.

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Living on the edge: Simulations of bacterial outer-membrane proteins

Cited by 40 publications

References 87 publications

Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

Reparameterization of Solute—Solute Interactions for Amino Acid–Sugar Systems Using Isopiestic Osmotic Pressure Molecular Dynamics Simulations

Outer membrane protein size and LPS O-antigen define protective antibody targeting to the Salmonella surface

How Do Short Chain Nonionic Detergents Destabilize G-Protein-Coupled Receptors?

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