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

Abstract

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.

Polarizable force field development for lipids and their efficient applications in membrane proteins

“…The CHEQ approach was also combined with enhanced sampling scheme to study the role of water in the permeation of an amino acid side‐chain analog, namely methyl guanidinium, across DPPC lipid bilayer membrane . The PMF estimated via umbrella sampling was further decomposed into contributions from various system components including water, lipids, and ions.…”

“…Via this analysis as well as investigating the water densities crossing the water–bilayer interface, it was proposed by the authors that the guanidinium crossing the lipid bilayer could be either stabilized or destabilized by the deformation of lipids and the effects of water molecules at the core of lipids. The results show in approximate agreement with those obtained from additive force field …”

Polarizable force fields for molecular dynamics simulations of biomolecules

“…Simulations of hydrated DPPC monolayers also suggested that the inclusion of polarizability results in an improved representation of the monolayer‐water potential difference relative to the water–air interface . Simulations with the CHEQ force field have also been used to probe the transfer of the methyl‐guanidinium cation across the bilayer‐water interface, giving results in approximate agreement with those obtained from previous, non‐polarizable, simulations …”

Investigating Hydrophilic Pores in Model Lipid Bilayers Using Molecular Simulations: Correlating Bilayer Properties with Pore-Formation Thermodynamics

“…15 The presence of a water pore is predicated on structural perturbations of the bilayer itself, and thus that study recapitulates a series of molecular dynamics studies highlighting the intimate connection between translocation of charged peptides in bilayers and some type of structural perturbation at the scales of single (or several) lipid molecules. 32,33 …”