Coarse-Grained Molecular Model for the Glycosylphosphatidylinositol Anchor with and without Protein

Banerjee, Prashant; Lipowsky, Reinhard; Santer, Mark

doi:10.1021/acs.jctc.0c00056

Cited by 12 publications

(12 citation statements)

References 62 publications

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“…For both the equilibration and production runs, the leapfrog stochastic dynamics integrator (sd) ( 80 ) was used and the temperature was kept at 310K with the v-rescale thermostat (τt = 1.0 ps). The relatively small timesteps were necessary to avoid numerical instabilities, and the Lennard-Jones potentials describing sugar-sugar and sugar-protein interactions were scaled down by a factor of 0.85 to prevent aggregation ( 76 ).…”

Section: Methodsmentioning

confidence: 99%

“…To model the native GPI anchor, we used published parameters for the sugars and lipid tails ( 76 ) and parameterized the linker specifically for CD59 using the same strategy outlined in ( 76 ). An atomistic molecule was built with the LEaP in Ambertools21 ( 77 ) comprising of the three C-terminal residues of CD59 (Leu-Glu-Asn) with an acetyl cap on the N-terminus of the leucine residue.…”

Section: Methodsmentioning

confidence: 99%

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Structural basis for membrane attack complex inhibition by CD59

Couves

Gardner

Voisin

et al. 2022

Preprint

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CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryoelectron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming 𝛽-hairpins of C8 to form an intermolecular 𝛽-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 𝛽-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structural basis for membrane attack complex inhibition by CD59

Couves

Gardner

Voisin

et al. 2022

Preprint

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“…GPI has a flexible pseudopentasaccharide glycan core Man-α(1-2)-Man-α(1-6)-Man-α(1→4)-GlcN-α(1-6)-Myo-inositol which is connected to a lipid tail. The conformational behavior of GPI and GPI-anchored green fluorescent protein (GFP) in the membrane surrounding has been studied using CG MD . In addition to the novel CG parameters of GPI, consistent with the Martini force field, the authors outlined the importance of polarizable water model usage.…”

Section: Glycans and Glycoconjugatesmentioning

confidence: 99%

“…The conformational behavior of GPI and GPI-anchored green fluorescent protein (GFP) in the membrane surrounding has been studied using CG MD. 260 In addition to the novel CG parameters of GPI, consistent with the Martini force field, the authors outlined the importance of polarizable water model usage.…”

Section: Structure Function and Dynamics Of Glycolipidsmentioning

confidence: 99%

Multifaceted Computational Modeling in Glycoscience

Pérez

Makshakova

2022

Chem. Rev.

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Glycoscience assembles all the scientific disciplines involved in studying various molecules and macromolecules containing carbohydrates and complex glycans. Such an ensemble involves one of the most extensive sets of molecules in quantity and occurrence since they occur in all microorganisms and higher organisms. Once the compositions and sequences of these molecules are established, the determination of their three-dimensional structural and dynamical features is a step toward understanding the molecular basis underlying their properties and functions. The range of the relevant computational methods capable of addressing such issues is anchored by the specificity of stereoelectronic effects from quantum chemistry to mesoscale modeling throughout molecular dynamics and mechanics and coarse-grained and docking calculations. The Review leads the reader through the detailed presentations of the applications of computational modeling. The illustrations cover carbohydrate−carbohydrate interactions, glycolipids, and N-and O-linked glycans, emphasizing their role in SARS-CoV-2. The presentation continues with the structure of polysaccharides in solution and solid-state and lipopolysaccharides in membranes. The full range of protein-carbohydrate interactions is presented, as exemplified by carbohydrate-active enzymes, transporters, lectins, antibodies, and glycosaminoglycan binding proteins. A final section features a list of 150 tools and databases to help address the many issues of structural glycobioinformatics. CONTENTS 5.1. N-and O-Linked Glycans 5.2. Structure and Dynamics of SARS-CoV-2 5.3. Structure, Function, and Dynamics of Glycolipids 6. Polysaccharides 6.1. Polysaccharides in Solution 6.2. Polysaccharides in the Solid-State 6.3. Lipolysaccharides in Membranes 7. Protein Carbohydrate Interactions 7.1. Presentation: Synopsis of the Protein Families 7.2. Insights into Glycosyltransferases 7.3. Insights into Glycosyl Hydrolases 7.4. Enzymatic Degradation of Polysaccharides in the Solid-State

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“…The CG mapping of AcxPIMx is shown in Figures 1B,C. The parameter files that describe the bonds, constraints, and angles were assembled based on the previously described data 32,34,35 as an initial estimate.…”

Section: Building the Coarse-grained Lipid Parametersmentioning

confidence: 99%

From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of theMycobacterialPlasma Membrane

Brown

Corey

Gao

et al. 2022

Preprint

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Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, a disease that claims ~1.5 million lives annually. The current treatment regime is long and expensive, and missed doses contribute to drug resistance. There is much to be understood about the Mtb cell envelope, a complicated barrier that antibiotics need to negotiate to enter the cell. Within this envelope, the plasma membrane is the ultimate obstacle and is proposed to be comprised of over 50% mannosylated phosphatidylinositol lipids (phosphatidyl-myoinositol mannosides, PIMs), whose role in the membrane structure remains elusive. Here we used multiscale molecular dynamics (MD) simulations to understand the structure-function relationship of the PIM lipid family and decipher how they self-organize to drive biophysical properties of the Mycobacterial plasma membrane. To validate the model, we tested known anti-tubercular drugs and replicated previous experimental results. Our results shed new light into the organization of the Mycobacterial plasma membrane and provides a working model of this complex membrane to use for in silico studies. This opens the door for new methods to probe potential antibiotic targets and further understand membrane protein function.

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Coarse-Grained Molecular Model for the Glycosylphosphatidylinositol Anchor with and without Protein

Cited by 12 publications

References 62 publications

Structural basis for membrane attack complex inhibition by CD59

Structural basis for membrane attack complex inhibition by CD59

Multifaceted Computational Modeling in Glycoscience

From Molecular Dynamics to Supramolecular Organization: The Role of PIM Lipids in the Originality of theMycobacterialPlasma Membrane

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