(692e) Improving the Lipid Force Field of CHARMM: A Quantum Mechanical and Experimental Approach

Biological membranes form a barrier to protect the cell from its environment and selectively control the entrance/exit of small molecules. Molecular simulations of these biological membranes require an accurate lipid force field (a major component of the membrane). Previously, extensive ab initio quantum mechanical (QM) calculations have been used to improve the aliphatic portion of the CHARMM27 lipid force field. Although this was a significant improvement, the lipid head group required additional modifications to agree with experimental lipid bilayer deuterium order parameters (S_CD) and solvation free energies. To improve the solvation free energies, we modified the atomic charges in the carbonyl-glycerol region. The S_CD's for the lipid head group of DPPC were improved by fitting dihedral energy terms to high-level QM calculations and/or to torsional conformational populations that result in agreement with experimental S_CD's. Molecular dynamics (MD) simulations with this new force field, referred to as CHARMM35 (C35), resulted in a significant improvement in the S_CD's and water hydration for DPPC lipid bilayers. The calculated electrostatic profile and lipid bilayer surface tension decreased significantly with the C35 force field. Consequently, the C35 force field resulted in excellent surface areas per lipid with NPT simulations, which is a significant improvement from the C27r force field that required constant area simulations (NPAT) to prevent some bilayers from laterally condensing. MD simulations of other lipid bilayers and monolayers also agreed favorably with experimental densities, monolayer surface tensions, and S_CD's, e.g., DMPC, DOPC, POPC, and POPE. Therefore, CHARMM35 is the pair-wise additive all atom force field of choice for lipids.