A Zoom on Membrane Fusion through Coarse-Grained, Atomistic and Hybrid Molecular Dynamics of SNARE Proteins

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The SNARE protein complex is central to membrane fusion. Modeling this system in order to better understand its guiding principles is a challenging task and requires the combination of original methods. We developed a hybrid representation mixing the SPC water model with a coarse grained (CG) model for solvation that can effectively mimic the hydration, structure, and dynamics of the SNARE membrane fusion complex, a trimeric protein-protein bundle embedded in a double phospholipid bilayer [1]. Comparison with a fully atomistic reference simulation illustrates the equivalence between both approaches.In this hybrid approach, bulk regions are treated at a CG level, while keeping the atomistic details around the solute. Since water represents about 80% of any biological system, this approach may offer a significant reduction in the computational cost of simulations without compromising atomistic details. In addition, we modeled the SNARE system at both CG level [2] and at full atomic detail [3]. By comparing a series of simulations where amino acid, membrane and electrolyte compositions are varied, we observe marked effects on bilayer curvature and deformations around the transmembrane domains, leading to a decreasing distance between them. If the link between membrane and bundle is severed, both membranes go back to a flat state.[1] Darre et al. Mixing atomistic and coarse grain solvation models for MD simulations: let WT4 handle the bulk. JCTC, 2012, DOI: 10.1021/ct3001816[2] Durrieu et al. Coarse-grain simulations of the R-SNARE fusion protein in its membrane environment detect long-lived conformational sub-states, ChemPhysChem 10, 2009, 1548-155.[3] Durrieu et al. Interactions between neuronal fusion proteins explored by molecular dynamics, Biophys.J.94, 2008, 3436-3446.Computing time was provided by the French supercomputer centers IDRIS and CINES (Projects No 2012071714 and LBT2411).