Mixed resolution models in which the proteins and ligands are represented atomistically while their environment, the membrane and aqueous solvent, are represented by coarse grain (CG) sites offer the advantage of capturing the intricate conformational changes with computational speedup. In this approach, the all atom � all atom (AA-AA) interactions between protein and ligand are defined using atomistic simulation force field parameters. The AA-CG and CG-CG interaction potentials between the protein, ligand and environment are obtained using the force matching algorithm followed by number of systematic manual adjustments to reproduce the key structural characteristics from the AA molecular dynamics simulation.The mixed resolution AA/CG force field parameters were first developed based on AA Adenosine A2A receptor bound to ZM241385 (ZMA) antagonist in a CG POPC membrane/water system.  The mixed resolution simulation of the GPCR was validated through secondary structure analysis as a function of time, cross RMSD plots, side-chain rotamer library analysis, density profiles and analysis of binding site. In order to enhance the robustness of the AA/CG force field parameters, we further refined them by testing the potentials on small antimicrobial peptides (AMPs) and globular proteins. The mixed resolution simulation of AA melittin (an AMP) monomer in CG bulk water and lipid bilayer was studied and validated through secondary structure analysis, Ramachandran plot and interaction with membrane.We have developed a consistent set of AA/CG potentials that can be applied across wide range of systems from small and simple AMPs to large and complex GPCRs. Additional fine tuning of the potentials is desirable. We are currently analyzing additional systems to include more types of atom and enhance sampling.

Mixed resolution molecular dynamics simulations of atomistic proteins in coarse grained environment

248th National Meeting (2014)

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