Validation of the charge equilibration lipid force field for simulations of phospholipid membranes with an application to the study of the free energetics of methyl guanidinium permeation across a DPPC bilayer

Patel, SandeepPrevious work in our group focused on the development and refinement of po-larizable charge equilibration (CHEQ) force fields for use in molecular dynamics (MD) simulations of phospholipid bilayers. We present results to further validate these force fields by extending to simulations of a model DPPC-water monolayer. Several physical and electrostatic properties have been calculated for comparison with previously re-ported experimental and computational studies including component density profiles, deuterium order parameters, surface pressure and tension, and the monolayer-water potential difference relative to a pure water-air interface. Having validated the CHEQ force field for use with both lipid bilayer and monolayer systems, as well as having identified areas where improvement is needed, we apply an intermediate, revised ver-sion of the force field to study the energetics of an arginine side-chain analog, methyl guanidinium, as it crosses a DPPC lipid bilayer. Combining umbrella sampling MD simulations with the Weighted Histogram Analysis Method (WHAM) for unbiasing probabilities, we compute a potential of mean force (PMF) for the reversible trans-fer of methyl guanidinium from bulk solution to bilayer center. Decomposition of the PMF in component contributions allows us to investigate the role of lipid and solvent to the energetics of permeation. Finally, through a series of simulations in which water is first prevented from entering the bilayer center where methyl guanidinium is restrained and then, after equilibration, allowed to enter the bilayer, we find that water perme-ation into the bilayer is required for the deformation of individual lipid molecules and permeation of ions into the membrane.University of Delaware, Department of Chemistry and BiochemistryM.S