Dual effect of cholesterol on interfacial water dynamics in lipid membranes: Interplay between membrane packing and hydration

TL;DR

This study investigates how cholesterol concentration modulates interfacial water dynamics in DPPC and PSM lipid membranes using all-atom MD simulations across $x_ ext{Chol}=0$, $0.1$, and $0.5$ at 303 K and 323 K. By partitioning the interfacial region into three zones (Region 1 interior, Region 2 interface, Region 3 bulk) and analyzing water density, orientation, and hydrogen-bonding, the authors demonstrate a nonmonotonic response: low Chol slows interfacial water dynamics in the ripple regime, while high Chol enhances water mobility and reduces hydrogen-bond lifetimes by approximately $0.5$–$0.7$ of the Chol-free case. The observed behavior results from a balance between Chol-induced membrane condensation and the dilution of hydrophilic headgroups, which at high Chol increases water penetration at the interface. These findings offer mechanistic insights for tuning interfacial hydration in membranes and highlight lipid-type–dependent effects linked to packing and headgroup structure.

Abstract

Water contained within biological membranes plays a critical role in maintaining the separation between intracellular and extracellular environments and facilitating biochemical processes. Variations in membrane composition and temperature lead to phase state changes in lipid membranes, which in turn influence the structure and dynamics of the associated interfacial water. In this study, molecular dynamics simulations were performed on binary membranes composed of dipalmitoylphosphatidylcholine (DPPC) or palmitoyl sphingomyelin (PSM) mixed with cholesterol (Chol). To elucidate the effects of Chol on interfacial water, we examined the orientation and hydrogen-bonding behavior of water molecules spanning from the membrane interior to the interface. As the Chol concentration increased, a transient slow down in water dynamics was observed in the ripple phase at 303 K. Conversely, at higher Chol concentrations, water dynamics were accelerated relative to pure lipid membranes across all temperatures studied. Specifically, at a Chol concentration of 50%, the hydrogen bond lifetime in DPPC membranes decreased to approximately 0.5-0.7 times that of pure lipid membranes. This nonmonotonic behavior is attributed to the combined effects of membrane packing induced by Chol and a reduced density of lipid molecules in the hydrophilic region, offering key insights for modulating the dynamical properties of interfacial water.

Figures (9)

• Figure 1: Structures of DPPC (a), PSM (b), and Chol (c) molecules studied in this paper.
• Figure 2: Snapshots of DPPC-Chol systems at 303 K, with DPPC shown in light blue, cholesterol in violet, phosphorus atoms in orange, and water in transparent blue. The upper panels present top-down views in the $xy$-plane with water omitted, while the lower panels show side views along the $z$-axis. All images were generated using the molecular visualization software VMD. humphrey1996VMD Panels correspond to (a) $x_\mathrm{Chol}=0$, (b) $x_\mathrm{Chol}=0.1$, and (c) $x_\mathrm{Chol}=0.5$.
• Figure 3: Area per lipid as a function of the molar fraction of Chol, $x_\mathrm{Chol}$, for (a) DPPC and (b) PSM. Circles (blue) and squares (pink) represent the results at 303 K and 323 K, respectively.
• Figure 4: (a) and (b): Ratios of the water molecule density distribution, $\rho(z')$, to the bulk water density, $\rho_\mathrm{bulk}= 33.50$ and 32.95 $\mathrm{nm}^{-3}$, for DPPC and PSM at 303 K, respectively. (c) and (d): Average numbers of H-bonds, $N_\mathrm{HB}$, as a function of $z'$, using the same axis as in (a) and (b), at 303 K. (e) and (f): $N_\mathrm{HB}$, normalized by the number of nearest neighbor oxygen atoms $N_\mathrm{NN}$, as a function of $z'$, using the same axis as in (a) and (b), at 303 K. The vertical dashed lines represent the boundaries separating the three regions.
• Figure 5: Left panel: Schematic illustration of water orientation. Right panels: Two-dimensional plots of joint distribution of $\rho(z',\cos\theta)$, normalized by $\rho(z')$, at 303K for $x_\mathrm{Chol}=0$ [(a) and (d)], 0.1 [(b) and (e)], and 0.5 [(c) and (f)]. Panels (a), (b), and (c) correspond to DPPC, while panels (d), (e), and (f) corresponds to PSM.