Simulations of lipid bilayers using the CHARMM36 force field with the TIP3P-FB and TIP4P-FB water models

Abstract

The CHARMM36 force field for lipids is widely used in simulations of lipid bilayers. The CHARMM family of force fields were developed for use with the mTIP3P water model. This water model has an anomalously high dielectric constant and low viscosity, which limits its accuracy in the calculation of quantities like permeability coefficients. The TIP3P-FB and TIP4P-FB water models are more accurate in terms of the dielectric constant and transport properties, which could allow more accurate simulations of systems containing water and lipids. To test whether the CHARMM36 lipid force field is compatible with the TIP3P-FB and TIP4P-FB water models, we have performed simulations of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayers. The calculated headgroup area, compressibility, order parameters, and X-ray form factors are in good agreement with the experimental values, indicating that these improved water models can be used with the CHARMM36 lipid force field without modification when calculating membrane physical properties. The water permeability predicted by these models is significantly different; the mTIP3P-model diffusion in solution and at the lipid-water interface is anomalously fast due to the spuriously low viscosity of mTIP3P-model water, but the potential of mean force of permeation is higher for the TIP3P-FB and TIP4P-FB models due to their high excess chemical potentials. As a result, the rates of water permeation calculated the FB water models are slower than the experimental value by a factor of 15-17, while simulations with the mTIP3P model only underestimate the water permeability by a factor of 3.

Keywords: Force field; Head group area; Lipid; Membrane permeability; Molecular dynamics; Molecular simulation; Scattering; Water model.

Figure 1. Schematics of the (A) mTIP3P, (B) TIP3P-FB, and (C) TIP4P-FB water models.

The electrostatic and Lennard-Jones parameters are listed beneath each model.

Figure 2. Chemical structure of (A) DPPC and (B) POPC, the two lipids modeled in this study.

Figure 3. A rendering of the simulation cell used in the simulations of POPC.

Figure 4. NMR deuterium order parameters (|S_CD|) for the lipid tails of the DPPC and POPC bilayers calculated from simulations of the bilayers with the mTIP3P, TIP3P-FB, and TIP4P-FB water models.

(A) and (B) show the profile for the first chain (sn-1), while the (C) and (D) shows the second chain (sn-2). Experimental values are reproduced from Seelig & Seelig (1974), Seelig & Waespe-Sarcevic (1978), Douliez, Léonard & Dufourc (1995), Li et al. (2017). In most cases, the values from the simulations are so similar that the points lie on top of each other. The numbering of the positions on the acyl chains is illustrated in Fig. 2.

Figure 5. NMR order parameters (S_CH) for the lipid headgroups of the (A) DPPC and (B) POPC bilayers calculated from simulations of the bilayers with the mTIP3P, TIP3P-FB, and TIP4P-FB water models.

Experimental values for DPPC are taken from Gally, Niederberger & Seelig (1975). Experimental values for POPC are taken from Ferreira et al. (2013). The assignments of the order parameters follow those presented in Botan et al. (2015). The labeling of the positions of the headgroup is illustrated in Fig. 2.

Figure 6. Electron density profile for (A) DPPC and (B) POPC bilayers calculated from simulations using the CHARMM36 lipid force field and the three water models.

The experimental curves are reproduced from Kučerka, Tristram-Nagle & Nagle (2006a, .

Figure 7. X-ray scattering profiles of (A) DPPC and (B) POPC lipid bilayers calculated from the simulated electron density profiles.

The experimental profile is reproduced from Kučerka et al. (2008).

Figure 8. Neutron scattering profiles of (A) DPPC and (B) POPC lipid bilayers calculated from the simulated neutron scattering length profiles.

The experimental profile is reproduced from Kučerka et al. (2008).

Figure 9. The membrane dipole potential (ϕ) calculated for the three water models of (A) DPPC and (B) POPC lipid bilayers.

The experimental values for DPPC from Gawrisch et al. (1992), Schamberger & Clarke (2002), and Peterson et al. (2002) are indicated by the gray horizontal lines.

Figure 10. The (A) PMF and (B) diffusivity profiles for a water molecule permeating a pure POPC bilayer at 298 K.