Simulating the Physiological Phase of Hydrated DPPC Bilayers: The Ester Moiety

Abstract The charge on the ester oxygen of the sn2 group of the dipalmitoylphosphatidylcholine (DPPC) has a remarkable effect on the square area per lipid in simulations of a hydrated bilayer. This is in contrast to simulations of nonpolar, neutral lipids, where it has been found to have little effect. The charges associated with the GROMOS96 45A3 and 45A4 biomolecular force fields have been previously shown to cause significant membrane shrinkage. We find that the use of larger charges at the ester groups alone (as opposed to on all the polar moieties in the head group) remedies the shrinkage. The source of this effect in DPPC lies in the fact that the charge distribution of this polar group profoundly influences its free energy of hydration and, correspondingly, the water distribution around it. In an attempt to rationally tune the ester parameters, the repulsive Lennard–Jones parameters that represent the van der Waals interaction have been refined to reproduce the experimental density and heat of vaporization, and the charges of the ester groups have been tuned to reproduce the experimental free energies of hydration of a series of alkane esters. The new parameters form part of the GROMOS96 53A5 and 53A6 force fields. However, with the new force‐field parameters, the area per lipid in simulations of hydrated DPPC bilayers lies below that of the physiological liquid‐crystalline phase, the implications of which are discussed.