Accurate simulation of biomolecular systems requires the consideration of solvation effects. The arrangement and dynamics of water close to a solute is strongly influenced by the solute itself. However, as the solute-solvent distance increases, the water properties tend to those of the bulk liquid. This suggests that bulk regions can be treated at a coarse grained (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. We show here that mixing the popular SPC water model with a CG model for solvation (called WatFour) can effectively mimic the hydration, structure and dynamics of molecular systems composed of pure water, simple electrolyte solutions and solvated macromolecules. As a non trivial example, we present simulations of the SNARE membrane fusion complex, a trimeric protein-protein complex embedded in a double phospholipid bilayer. Comparison with a fully atomistic reference simulation illustrates the equivalence between both approaches.

Leonardo Darre, Alex Tek, Marc Baaden, and Sergio Pantano in J. Chem. Theory Comput., Just Accepted Manuscript
DOI: 10.1021/ct3001816 - Publication Date (Web): June 4, 2012 - http://pubs.acs.org/doi/abs/10.1021/ct3001816

Balises : research, InEnglish

Pentameric ligand-gated ion channels mediate signal transduction through conformational transitions between closed-pore and open-pore states. To stabilize a closed conformation of GLIC, a bacterial proton-gated homolog from Gloeobacter violaceus whose open structure is known, we separately generated either four cross-links or two single mutations. We found all six mutants to be in the same 'locally closed' conformation using X-ray crystallography, sharing most of the features of the open form but showing a locally closed pore as a result of a concerted bending of all of its M2 helices. The mutants adopt several variant conformations of the M2-M3 loop, and in all cases an interacting lipid that is observed in the open form disappears. A single cross-linked mutant is functional, according to electrophysiology, and the locally closed structure of this mutant indicates that it has an increased flexibility. Further cross-linking, accessibility and molecular dynamics data suggest that the locally closed form is a functionally relevant conformation that occurs during allosteric gating transitions.

By Marie S Prevost, Ludovic Sauguet, Hugues Nury, Catherine Van Renterghem, Christèle Huon, Frederic Poitevin, Marc Baaden, Marc Delarue & Pierre-Jean Corringer
Published online at NATURE STRUCTURAL & MOLECULAR BIOLOGY | http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2307.html

Balises : research, InEnglish