Ion pair amphiphile (IPA), a molecular complex composed of a pair of cationic and anionic amphiphiles, is an inexpensive phospholipid substitute to fabricate vesicles with various pharmaceutical applications. Modulating the physicochemical and permeation properties of IPA vesicles are important for carrier designs. Here, we applied molecular dynamics simulations to examine the cholesterol effects on the structures, mechanics, and water permittivity of hexadecyltrimethylammonium-dodecylsulfate (HTMA-DS) and dodecyltrimethylammonium- hexadecylsulfate (DTMA-HS) IPA bilayers. Structural and mechanical analyses indicate that both IPA systems are in gel phase at 298 K. Adding cholesterol induces alkyl chain ordering around the rigid sterol ring and increases the cavity density within the hydrophilic region of both IPA bilayers. Furthermore, the enhanced alkyl chain ordering and the membrane deformation energy induced by cholesterol increase the permeation free energy penalty. In contrast, cholesterol has minor effects on the water local diffusivities within IPA membranes. Overall, the cholesterol reduces the water permittivity of rigid IPA membranes due to the synergistic effects of increased alkyl chain ordering and enhanced membrane mechanical modulus. The results provide molecular insights into the effects of molecular packing and mechanical deformations on the water permittivity of biomimetic IPA membranes, which is critical for designing IPA vesicular carriers.

One of the challenging applications of molecular dynamics (MD) simulations is to determine the dynamic properties such as the diffusion coefficient of the molecule of interest, particularly slow dynamic systems such as hydrogels and polymer melts. Recently, Neyertz et al. proposed a trajectory- extending kinetic Monte Carlo (TEKMC) algorithm combining both MD and kinetic Monte Carlo to probe the penetrant diffusion within the glassy polymer systems (S. Neyertz and D. Brown, Macromolecules 43, 9210, 2010). Yet, the original TEKMC relies on the manual adjustments of the key parameters of the sampling interval τ and the discretizing grid size rgrid, which limits its applicability to systems with unknown kinetic properties. Here, we reviewed the theoretical background of kinetic Monte Carlo to establish the generic criteria for selecting TEKMC parameters. Also, we modified and expanded the TEKMC algorithm for bulk fluid systems. The modified TEKMC algorithm were applied to systems with various kinetic properties, including Lennard Jones liquid, bulk water, Li+ liquid electrolyte, and Li+ polymer electrolyte. The diffusion coefficients obtained from the modified TEKMC and the generic parameter selections were promising and robust compared with the conventional MD results. With the proposed TEKMC approach, one can extend the MD trajectories to unambiguously characterize the diffusion behavior in the long-time diffusive regime.