Free energetics and the role of water in the permeation of methyl guanidinium across the bilayer-water interface: insights from molecular dynamics simulations using charge equilibration potentials.

Combining umbrella sampling molecular dynamics (MD) simulations, the weighted histogram analysis method (WHAM) for unbiasing probabilities, and polarizable charge equilibration force fields, we compute the potential of mean force for the reversible transfer of methyl guanidinium from bulk solution to the center of a model DPPC bilayer. A 5 kcal/mol minimum in the potential of mean force profile for membrane permeation suggests that the analogue will preferentially reside in the headgroup region of the lipid, qualitatively in agreement with previously published results. We find the potential of mean force for permeation to be approximately 28 kcal/mol (relative to the minimum in the headgroups), within the range of values reported for similar types of simulations using fixed-charge force fields. From analysis of the lipid structure, we find that the lipid deformation leads to a substantial destabilizing contribution to the free energy of the methyl guanidinium as it resides in the bilayer center, though this deformation allows more efficient stabilization by water defects and transient pores. Water in the bilayer core stabilizes the charged residue. The role of water in stabilizing or destabilizing the solute as it crosses the bilayer depends on bulk electrolyte concentration. In 1 M KCl solution, the water contribution to the potential of mean force is stabilizing over the entire range of the permeation coordinate, with the sole destabilizing force originating from the anionic species in solution. Conversely, methyl guanidinium experiences net destabilization from water in the absence of electrolyte. The difference in solvent contributions to permeation free energy is traced to a local effect arising from differences in water density in the bilayer-water solution interface, thus leading to starkly opposite net forces on the permeant. The origin of the local water density differential rests with the penetration of hydrated chloride anions into the solution-bilayer interface. Finally, water permeation into the bilayer is required for the deformation of individual lipid molecules and permeation of ions into the membrane. From simulations where water is first excluded from the bilayer center where methyl guanidinium is restrained and then, after equilibration, allowed to enter the bilayer, we find that in the absence of any water defects/permeation into the bilayer, the lipid headgroups do not follow the methyl guanidinium. Only when water enters the bilayer do we see deformation of individual lipid molecules to associate with the amino acid analogue at bilayer center.