CHARMM36 Lipid Force Field with Explicit Treatment of Long-Range Dispersion: Parametrization and Validation for Phosphatidylethanolamine, Phosphatidylglycerol, and Ether Lipids.

Abstract

Long-range Lennard-Jones (LJ) interactions have been incorporated into the CHARMM36 (C36) lipid force field (FF) using the LJ particle-mesh Ewald (LJ-PME) method in order to remove the inconsistency of bilayer and monolayer properties arising from the exclusion of long-range dispersion [Yu, Y.; Semi-automated Optimization of the CHARMM36 Lipid Force Field to Include Explicit Treatment of Long-Range Dispersion. J. Chem. Theory Comput. 2021, 10.1021/acs.jctc.0c01326. (preceding article in this issue)]. The new FF is denoted C36/LJ-PME. While the first optimization was based on three phosphatidylcholines (PCs), this work extends the validation and parametrization to more lipids including PC, phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and ether lipids. The agreement with experimental structure data is excellent for PC, PE, and ether lipids. C36/LJ-PME also compares favorably with scattering data of PG bilayers but less so with NMR deuterium order parameters of 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DMPG) at 303.15 K, indicating a need for future optimization regarding PG-specific parameters. Frequency dependence of NMR T1 spin-lattice relaxation times is well-described by C36/LJ-PME, and the overall agreement with experiment is comparable to C36. Lipid diffusion is slower than C36 due to the added long-range dispersion causing a higher viscosity, although it is still too fast compared to experiment after correction for periodic boundary conditions. When using a 10 Å real-space cutoff, the simulation speed of C36/LJ-PME is roughly equal to C36. While more lipids will be incorporated into the FF in the future, C36/LJ-PME can be readily used for common lipids and extends the capability of the CHARMM FF by supporting monolayers and eliminating the cutoff dependence.