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.; et al. 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 T 1 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.

Physical Characterization of Triolein and Implications for Its Role in Lipid Droplet Biogenesis

“…Recently, a LJ cutoff-free version of C36 (C36/LJ-PME) was released. [45][46] The second TG model was made based on the C36/LJ-PME parameters in the same fashion used in the first model. However, both first and second models suffer from the low surface tension at the water interface (Fig.…”

“…Of note, DAG is also not included in the original C36 force field release; nonetheless, the CHARMM-GUI developers (The Im group) created a new topology for DAG based on the existing parameter set. All simulations were run by GROMACS 2018 and 2020 47 with the C36 43 , C36/LJ-PME [45][46] , or C36/LJ-PME-r force field. Simulations using C36 used the 1.2 nm LJ cutoff distance with a force-switching function between 1.0 nm to 1.2 nm, unless otherwise noted.…”

Re-charging your fats: Charmm36 parameters for neutral lipids triacylglycerol and diacylglycerol

“…Fortunately, a solution to this problem has been recently proposed via the use of a PMElike treatment of the Lennard-Jones interactions in C36 (LJ-PME) (Yu et al 2021b, a). We thus opted to also develop C36 LJ-PME compatible parameters for TGs and DGs.…”

“…However, this is a well-known issue of the C36 lipid model (Yu et al 2021b, a) that, as shown for several alkanes and oils (Leonard et al 2018), originates from the cutoff-based treatment of LJ interactions.…”

Accurate Simulations of Lipid Monolayers Require a Water Model With Correct Surface Tension

“…[12][13][14] This discrepancy has been suggested to arise from underestimated water-air surface tension of common water models 14,15 and the truncation of long-range van der Waals interactions which compromises the description of acyl chainvacuum interface. 13,16,17 We have recently demonstrated that the CHARMM36 ("C36" from now on) lipid model 13 combined with the 4-point OPC water model ("OPC4" from now on) 18 provides nearly quantitative agreement with experimental surface pressure-area isotherms of both singlecomponent 15 and multi-component 19 lipid monolayers. This is because OPC4 water model reproduces the surface tension of water with a Lennard-Jones (LJ) cuto↵ of 1.2-1.4 nm that is consistent with common lipid models such as the C36 13 and Slipids 20 ones.…”