Optimization of Slipids Force Field Parameters Describing Headgroups of Phospholipids

The
molecular mechanics force field Slipids developed in a series
of works by Jämbeck and Lyubartsev (J. Phys. Chem.
B 2012, 116, 3164–3179; J. Chem. Theory Comput. 2012, 8, 2938–2948) generally provides a good description of various
lipid bilayer systems. However, it was also found that order parameters
of C–H bonds in the glycerol moiety of the phosphatidylcholine
headgroup deviate significantly from NMR results. In this work, the
dihedral force field parameters have been reparameterized in order
to improve the agreement with experiment. For this purpose, we have
computed energies for a large amount of lipid headgroup conformations
using density functional theory on the B3P86/cc-pvqz level and optimized
dihedral angle parameters simultaneously to provide the best fit to
the quantum chemical energies. The new parameter set was validated
for three lipid bilayer systems against a number of experimental properties
including order parameters, area per lipid, scattering form factors,
bilayer thickness, area compressibility and lateral diffusion coefficients.
In addition, the order parameter dependence on cholesterol content
in the POPC bilayer was investigated. It is shown that the new force
field significantly improves agreement with the experimental order
parameters for the lipid headgroup while keeping good agreement with
other experimentally measured properties.