A Modified Lipid Force Field for Charmm: Development and Application to Single-Celled Organism Membranes

Abstract

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 (SCD) and solvation free energies. Therefore, we modified the atomic charges in the carbonyl-glycerol region and fit dihedral energy terms to high-level QM calculations and/or experiment. Molecular dynamics (MD) simulations with this new force field, referred to as CHARMM36 (C36), resulted in a significant improvement to the SCD's and water hydration for DPPC lipid bilayers. The calculated electrostatic profile and lipid bilayer surface tension decreased significantly. Consequently, the C36 force field resulted in excellent surface areas per lipid (and other properties) 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 pure lipid bilayers and monolayers also agreed favorably with experimental densities, monolayer surface tensions, and SCD's. The success of the C36 force field allowed for the study of complex lipid membranes in single-celled organisms. Model membranes were developed and simulated for yeast (six phospholipids, cholesterol, and 25-hydroxysterol) and Chlamydia (five unbranched lipids, a branced lipid, and cholesterol). These membranes are currently being used to study intracellular sterol transport and a porin protein that induces an immune response.