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. 2010 Jun 17;114(23):7830-43.
doi: 10.1021/jp101759q.

Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types

Jeffery B Klauda  1 , Richard M Venable, J Alfredo Freites, Joseph W O'Connor, Douglas J Tobias, Carlos Mondragon-Ramirez, Igor Vorobyov, Alexander D MacKerell Jr, Richard W Pastor
Affiliations

Update of the CHARMM all-atom additive force field for lipids: validation on six lipid types

Jeffery B Klauda et al. J Phys Chem B. .

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 semiempirical 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 (S(CD)) are well predicted with the new FF, including proper splitting of the S(CD) for the aliphatic carbon adjacent to the carbonyl for DPPC, POPE, and POPC bilayers. The area compressibility modulus and frequency dependence of (13)C 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 lipid systems as well as heterogeneous systems including membrane proteins.

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Figures

Figure 1
Figure 1
Model compounds used in the present study including methylacetate (MAS), dimethylphosphate (DMP), ethyltrimethylammonium (ETMA), choline, 2-hexene, isopropylbutyrate (IPB), propylbutyrate (PB), propylmethylphosphate (PMP), an esterified glycerol analog ((M)EGLY), an esterified glycerol-phosphate analog ((M)PGLY) and the general structure of DPPC. For the esterified glycerol analogs, the parenthesis on the compound and the (M) indicate the extension of the aliphatic chain by a methylene as required to investigate the conformational energetics of the β3 and γ3 dihedrals using the model compounds MEGLY and MPGLY. DPPC is also shown with torsions labeled in red and corresponding labels for carbons used in comparison with NMR experiments.
Figure 2
Figure 2
Dihedral scans for the α4, γ1 and γ3 torsions based on model compounds (MEGLY and PMP). The energy at 180° is set as the zero for γ3 and α4 and 60° for γ1.
Figure 3
Figure 3
NMR deuterium order parameters (SCD) for a DPPC bilayer from experiment– and NPAT simulations with A=64 Å2/lipid, which is close the experimental surface area.
Figure 4
Figure 4
Contour maps of potentials of mean force from simulations for the glycerol torsions in hydrated DPPC bilayers for C27r and C36. Contours are at 1 kcal/mol intervals, with the red lines 1 kcal/mol above the global minimum for each surface.
Figure 5
Figure 5
Surface areas versus time for the seven lipid systems considered in this study. Medium dashed lines show experimental values with dotted lines for mean ± standard error; heavy solid lines show the cumulative average beginning at 5 ns. Unless noted, all systems are at high hydration.
Figure 6
Figure 6
Form factors of DPPC (top) and DMPC (bottom) bilayers from experiment, and MD simulations. For DPPC, the NPAT simulations are labeled with A64 for 64 Å2/lipid. For DMPC, the C27r simulations were run in the NPAT ensemble with 60.7 Å2/lipid (A60.7) and the C36 simulations were run with the NPT ensemble.
Figure 7
Figure 7
Electron density of a DPPC bilayer from an experimental structural model (SDP) and MD simulations. NPT simulations with PME are labeled as NPT and constant surface area (64 Å2/lipid) is labeled as A64.
Figure 8
Figure 8
Lipid chain relaxation rates (1/NT1) for a DPPC bilayer as a function of Larmor frequency (ωc)−1/2. Simulation relaxation rates for C36 are calculated using the NPT ensemble and compared to previous C27r (NPAT) and C27 (NPAT) results. These are compared with measurements with multilayers and sonicated vesicles.
Figure 9
Figure 9
NMR deuterium order parameters (SCD) for POPC and POPE bilayers. For the MD simulations the sn-1 and sn-2 chains are in blue and green, respectively. The solid lines are based on results from NPT simulations with C36 and the dashed lines based on NP(A=60)T with C27r for POPE. Experiment is shown in red: the sn-1 (308 K) chain is in open triangles and sn-2 (310 K) chain in open squares.
Figure 10
Figure 10
Electron density of a DOPC bilayer from an experimental structural model (SDP) and MD simulations. NPT simulations are in black and the SDP model is in red.
Figure 11
Figure 11
Water distributions in DOPC bilayers at low hydration from neutron diffraction experiments and NPT simulations. The experimental Gaussian distribution for a single bilayer leaflet is compared to C36 and C27 simulations.
Figure 12
Figure 12
(top) The orientation of the water dipole with respect to the positive z-axis, scaled by the electron density for the DPPC bilayer at constant surface (64 Å2/lipid, A64) and NPT simulations. Simulations with the C27r FF were run at NP(A=64)T. The electrostatic potential drop for the bilayer simulations is shown in the bottom panel.
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