Effects of Cholesterol on Water Permittivity of Biomimetic Ion Pair Amphiphile Bilayers: Interplay between Membrane Bending and Molecular Packing

Abstract

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.

Keywords: biomimetic membrane; cholesterol; ion pair amphiphile; molecular dynamics; water permeation.

Figure 1

Molecular structures of HTMA-DS, DTMA-HS IPA complexes, and cholesterol. The representative bilayer structures of pure IPA and IPA-Chol systems are also shown, where the molecule color codes are: alkyltrimethylammonium in blue, alkylsulfate in yellow, and cholesterol in red. Graphics were generated using VMD package [30].

Figure 2

The deuterium order parameter ($|{\mathrm{S}}_{\mathrm{CD}}|$) profiles at various X${}_{\mathrm{chol}}$ of (a) HTMA and (b) DS components for HTMA-DS-Chol systems and (c) DTMA and (d) HS components for DTMA-HS-Chol systems are shown in top panels. Also, the gauche fraction profiles at various X${}_{\mathrm{chol}}$ along the alkyl chains of (e) HTMA and (f) DS components for HTMA-DS-Chol systems and (g) DTMA and (h) HS components for DTMA-HS-Chol systems are shown in bottom panels.

Figure 3

Cavity density profile ${\mathrm{P}}_{\mathrm{cav}}\left(\mathrm{z}\right)$ of (a) HTMA-DS-Chol and (b) DTMA-HS-Chol bilayers at various X${}_{\mathrm{chol}}$ with the standard deviations of less than 0.015. Error bars are not shown for clarity.

Figure 4

Three mechanical moduli for HTMA-DS-Chol (black circle) and DTMA-HS-Chol (red square) bilayers at various X${}_{\mathrm{chol}}$: (a) the area compressibility modulus $K_A$, (b) molecular tilt modulus $\chi$, and (c) bending modulus $K_C$.

Figure 5

The free energy profiles (top panels) and the membrane bending energy profiles during water permeation for (a) HTMA-DS-Chol and (b) DTMA-HS-Chol bilayers at various X${}_{\mathrm{chol}}$. In addition (c) the representative membrane surface with maximum bending energy at z = 1.2 nm, and the superimposition of the surface with the bilayer structure where the permeant water oxygen is labeled with red sphere. Graphics were generated using VMD package [30].

Figure 6

The local diffusivity profiles $D\left(z\right)$ of the permeant water for (a) HTMA-DS-Chol and (b) DTMA-HS-Chol bilayers at various X${}_{\mathrm{chol}}$.

Figure 7

The local permeation resistance profiles $R_{local}\left(z\right)$ for (a) HTMA-DS-Chol and (b) DTMA-HS-Chol bilayers at various X${}_{\mathrm{chol}}$.

Figure 8

The water permittivity coefficients for HTMA-DS-Chol (black circle) and DTMA-HS-Chol (red square) bilayers as a function of cholesterol concentration X${}_{\mathrm{chol}}$.