Update of the CHARMM All-Atom Additive Force Field for Lipids: Validation on Six Lipid Types

Abstract

A significant modification to the additive all-atom CHARMM lipid force field (FF) is developed and applied to phospholipid bilayers with both choline and ethanolamine containing head groups and with both saturated and unsaturated aliphatic chains. Motivated by the current CHARMM lipid FF (C27 and C27r) systematically yielding values of the surface area per lipid that are smaller than experimental estimates and gel-like structures of bilayers well above the gel transition temperature, selected torsional, Lennard-Jones and partial atomic charge parameters were modified by targeting both quantum mechanical (QM) and experimental data. QM calculations ranging from high-level ab initio calculations on small molecules to semi-empirical QM studies on a 1,2-dipalmitoyl-sn-phosphatidylcholine (DPPC) bilayer in combination with experimental thermodynamic data were used as target data for parameter optimization. These changes were tested with simulations of pure bilayers at high hydration of the following six lipids: DPPC, 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), 1,2-dilauroyl-sn-phosphatidylcholine (DLPC), 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2-dioleoyl-sn-phosphatidylcholine (DOPC), and 1-palmitoyl-2-oleoyl-sn-phosphatidylethanolamine (POPE); simulations of a low hydration DOPC bilayer were also performed. Agreement with experimental surface area is on average within 2%, and the density profiles agree well with neutron and x-ray diffraction experiments. NMR deuterium order parameters (SCD) are well predicted with the new FF, including proper splitting of the SCD for the aliphatic carbon adjacent to the carbonyl for DPPC, POPE, and POPC bilayers. The area compressibility modulus and frequency dependence of 13C NMR relaxation rates of DPPC, and the water distribution of low hydration DOPC bilayers also agree well with experiment. Accordingly, the presented lipid FF, referred to as C36, allows for molecular dynamics simulations to be run in the tensionless ensemble (NPT), and is anticipated to be of utility for simulations of pure lipids systems as well as heterogeneous systems including membrane proteins.

Molecular Structures of Fluid Phosphatidylethanolamine Bilayers Obtained from Simulation-to-Experiment Comparisons and Experimental Scattering Density Profiles

“…However, our simulations yielded an average PE area per lipid of 53.2 Å 2 and displayed lipid chain order characteristic of a gel phase. At first, this appears to be in contrast to the 59.2 Å 2 (although still decreasing after 40 ns) reported by Klauda et al for T = 310.15 K. 42 However, subsequent publications from Klauda and Pastor, 28 and posts on simulation community forums, 48 suggested a fix to the problem through force-based cut-offs, as was the case in the original simulations performed using the NAMD and CHARMM software. Our results of such simulations equilibrated at an area per lipid of 55.4 Å 2 , and showed no signs of gelation.…”

“…Finally, a 1.4 nm cutoff was used for the short-range electrostatic and van der Waals interactions. ■ RESULTS AND DISCUSSION MD simulations of a fluid phase POPE bilayer at 35°C were first performed using the updated CHARMM36 42 force field under NPT conditions, i.e., lateral area was unconstrained. However, our simulations yielded an average PE area per lipid of 53.2 Å 2 and displayed lipid chain order characteristic of a gel phase.…”

Structure of the full-length glucagon class B G-protein-coupled receptor

“…Three parallel MD simulations were performed using the GROMACS 5.0.4 package 37 with isothermal–isobaric (NPT) ensemble and periodic boundary condition. The CHARMM36-CAMP force field 38 was used for the protein, the POPC phospholipids, ions and water molecules. Energy minimizations were first performed to relieve unfavorable contacts in the system, followed by equilibration steps of 50 ns in total to equilibrate the lipid bilayer and the solvent with restraints on the main chain of GCGR.…”

Sphingolipids contribute to acetic acid resistance in Zygosaccharomyces bailii

“…The DOPC force field was already available (Jämbeck and Lyubartsev, 2012b), and force fields for IPC, POPI, and ergosterol were developed based on established protocols (Jämbeck and Lyubartsev, 2012a, 2012b, 2013). Bonded and van der Waals parameters were taken from the CHARMM lipid force field (Klauda et al, 2010), and the charges were derived as follows. The charges on the lipid tails were taken from the Slipid force field, as the alkyl chains of all lipids have the same charges.…”