Excessive aggregation of membrane proteins in the Martini model

Javanainen, Matti; Martinez‐Seara, Hector; Vattulainen, Ilpo

doi:10.1371/journal.pone.0187936

Cited by 175 publications

(203 citation statements)

References 75 publications

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“…Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse-grained level. [40,41] Part of the work of VK was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) -Projektnummer 190586431 -SFB 974 "Communication and Systems Relevance in Liver Injury and Regeneration" (Düsseldorf, Germany) (project B01). HG is grateful for computational support and infrastructure provided by the "Zentrum für Informations-und Medientechnologie" (ZIM) at the Heinrich Heine University Düsseldorf and the computing time provided by the John von Neumann Institute for Computing (NIC) on the supercomputer JURECA at Jülich Supercomputing Centre (JSC) (user IDs: HKF7, HDD15; project IDs: 10766, 11761).…”

Section: Discussionmentioning

confidence: 99%

“…[33] Yet, despite recent advances in the development of coarse-grained force fields [34][35][36][37] and in the coarsegrained representation of protein-lipid interactions, [38,39] the proper energetic representation of protein association at the coarse-grained level is still debated. [40,41] From the PMF of dimerization, we computed binding free energies [42] and equilibrium association constants using a scheme applied to coarse-grained simulations of GPCR dimerization. [32,43] This approach has also been applied to study small-molecule binding to proteins.…”

Section: Introductionmentioning

confidence: 99%

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Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

et al. 2019

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We describe the first extensive energetic evaluation of GPCR dimerization on the atomistic level by means of potential of mean force (PMF) computations and implicit solvent/implicit membrane end‐point free energy calculations (MM‐PBSA approach). Free energies of association computed from the PMFs show that the formation of both the 1/8 and 4/5 interface is energetically favorable for TGR5, the first GPCR known to be activated by hydrophobic bile acids and neurosteroids. Furthermore, formation of the 1/8 interface is favored over that of the 4/5 interface. Both results are in line with our previous FRET experiments in live cells. Differences in lipid‐protein interactions are identified to contribute to the observed differences in free energies of association. A per‐residue decomposition of the MM‐PBSA effective binding energy reveals hot spot residues specific for both interfaces that form clusters. This knowledge may be used to guide the design of dimerization inhibitors or perform mutational studies to explore physiological consequences of distorted TGR5 association. Finally, we characterized the role of Y111, located in the conserved (D/E)RY motif, as a facilitator of TGR5 interactions. The types of computations performed here should be transferable to other transmembrane proteins that form dimers or higher oligomers as long as good structural models of the dimeric or oligomeric states are available. Such computations may help to overcome current restrictions due to an imperfect energetic representation of protein association at the coarse‐grained level. © 2019 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

et al. 2019

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“…We further used a scaling factor α to adjust the strength of protein-protein interactions. As described in previous studies, 48,49 the van der Waals parameters for interactions between different proteins are multiplied by this scaling factor α. In detail, the scaled well-depth ε scaled between two MARTINI beads is calculated as 3 | RESULTS…”

Section: Protocol Of Cg MD Simulationmentioning

confidence: 99%

“…As a result, α = 1 gives the original MARTINI beadbead interactions, while α = 0 gives the weakest MARTINI bead-bead interactions. The most commonly used scaling factors in the literature are 0.249 and 0.8,48 which were applied in this study.In the CG simulations, each system was equilibrated for 5 ns using the Berendsen thermostat and barostat before a production run. Theproduction run was performed with a time step of 20 fs.…”

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confidence: 99%

Computational simulations of TNF receptor oligomerization on plasma membrane

2019

Proteins

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The interactions between tumor necrosis factors (TNFs) and their corresponding receptors (TNFRs) play a pivotal role in inflammatory responses. Upon ligand binding, TNFR receptors were found to form oligomers on cell surfaces. However, the underlying mechanism of oligomerization is not fully understood. In order to tackle this problem, molecular dynamics (MD) simulations have been applied to the complex between TNF receptor‐1 (TNFR1) and its ligand TNF‐α as a specific test system. The simulations on both all‐atom (AA) and coarse‐grained (CG) levels achieved the similar results that the extracellular domains of TNFR1 can undergo large fluctuations on plasma membrane, while the dynamics of TNFα‐TNFR1 complex is much more constrained. Using the CG model with the Martini force field, we are able to simulate the systems that contain multiple TNFα‐TNFR1 complexes with the timescale of microseconds. We found that complexes can aggregate into oligomers on the plasma membrane through the lateral interactions between receptors at the end of the CG simulations. We suggest that this spatial organization is essential to the efficiency of signal transduction for ligands that belong to the TNF superfamily. We further show that the aggregation of two complexes is initiated by the association between the N‐terminal domains of TNFR1 receptors. Interestingly, the cis‐interfaces between N‐terminal regions of two TNF receptors have been observed in the previous X‐ray crystallographic experiment. Therefore, we provide supportive evidence that cis‐interface is of functional importance in triggering the receptor oligomerization. Taken together, our study brings insights to understand the molecular mechanism of TNF signaling.

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“…Since the peptide-peptide interactions might be overestimated in coarse-grained simulations (53), we performed additional all-atom simulations starting from preformed dimers. In agreement with our coarse-grained simulations, we found that parallel heterodimers were stable on the simulated timescale.…”

Section: Effects Of Peptide Dimersmentioning

confidence: 99%

Magainin 2 and PGLa in Bacterial Membrane Mimics I: Peptide-Peptide and Lipid-Peptide Interactions

Pachler

Kabelka

Appavou

et al. 2019

Preprint

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We addressed the onset of synergistic activity of the two well-studied antimicrobial peptides magainin 2 (MG2a) and PGLa using lipid-only mimics of Gram-negative cytoplasmic membranes. Specifically, we coupled a joint analysis of small-angle X-ray and neutron scattering experiments on fully hydrated lipid vesicles in the presence of MG2a and L18W-PGLa to all-atom and coarse-grained molecular dynamics simulations. In agreement with previous studies both peptides, as well as their equimolar mixture, were found to remain in a surface-aligned topology upon membrane insertion and to induce significant membrane perturbation as evidenced by membrane thinning and hydrocarbon order parameter changes in the vicinity of the inserted peptide. These effects were particularly pronounced for the so called synergistic mixture of 1:1 (mol/mol) L18W-PGLa/MG2a and cannot be accounted for by a linear combination of the membrane perturbations of two peptides individually. Our data are consistent with parallel heterodimers forming at much lower concentrations than previously considered, but which do not induce a synergistic leakage of dyes. Our simulations further show that the heterodimers interact via salt bridges and hydrophobic forces, which apparently makes them more stable than putatively formed antiparallel L18W-PGLa and MG2a homodimers. Moreover, dimerization of L18W-PGLa and MG2a leads to a relocation of the peptides within the lipid headgroup regime as compared to the individual peptides. The early onset of dimerization of L18W-PGLa and MG2a at low peptide concentrations consequently appears to be key to their synergistic dye-releasing activity from lipid vesicles at high concentrations . STATEMENT OF SIGNIFICANCEWe demonstrate that specific interactions of the antimicrobial peptides MG2a and PGLa with each other in POPE/POPG bilayers lead to the formation of surface-aligned parallel dimers, which provide already at low peptide concentrations the nucleus for the peptides' well-known synergistic activity.

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Excessive aggregation of membrane proteins in the Martini model

Cited by 175 publications

References 75 publications

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

Dimerization energetics of the G‐protein coupled bile acid receptor TGR5 from all‐atom simulations

Computational simulations of TNF receptor oligomerization on plasma membrane

Magainin 2 and PGLa in Bacterial Membrane Mimics I: Peptide-Peptide and Lipid-Peptide Interactions

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