Cholesterol plays an important role in regulating the properties of phospholipid membranes. To obtain a detailed understanding of the lipid-cholesterol interactions, we have developed a mesoscopic water-lipid-cholesterol model. In this model, we take into account the hydrophobic-hydrophilic interactions and the structure of the molecules. We compute the phase diagram of dimyristoylphosphatidylcholine-cholesterol by using dissipative particle dynamics and show that our model predicts many of the different phases that have been observed experimentally. In quantitative agreement with experimental data our model also shows the condensation effect; upon the addition of cholesterol, the area per lipid decreases more than one would expect from ideal mixing. Our calculations show that this effect is maximal close to the main-phase transition temperature, the lowest temperature for which the membrane is in the liquid phase, and is directly related to the increase of this main-phase transition temperature upon addition of cholesterol. We demonstrate that no condensation is observed if we slightly change the structure of the cholesterol molecule by adding an extra hydrophilic head group or if we decrease the size of the hydrophobic part of cholesterol.biomembrane ͉ molecular simulation ͉ phase behavior ͉ dimyristoylphosphatidylcholine ͉ mesoscopic model I n this article we address a seemingly simple thermodynamic question: how does the area per molecule of a phospholipid membrane change if we add cholesterol? This question was first posed by Leathes (1) in 1925 and is still being discussed today. The significance of this question relates directly to the importance of cholesterol for the functioning of membranes of higher eukaryotes. For example, cholesterol regulates the fluidity of the membrane and modulates the function of membrane proteins (2). Understanding these mechanisms has motivated many researchers to investigate the lipid-cholesterol interactions in detail. Because a membrane can be seen as a 2D liquid, a first estimate of how the area per molecule would change upon the addition of cholesterol would be to assume ideal mixing, where the area per molecule is simply a weighted average of the pure-components areas. In 1925 Leathes showed that, instead of ideal mixing, one observes a striking nonideal behavior (1). This nonideal behavior is called the condensing effect (3) because the area per molecule is much lower compared with ideal mixing. Because a membrane behaves as an incompressible fluid, a decrease of the area per molecule will result in a corresponding significant increase of the total thickness of the bilayer. Such an increase of the thickness signals a reorganization of the structure of the membrane. Because changes in the structure of the membrane may have important consequences for the functioning of proteins (2), it is important to have a better molecular understanding of the cholesterol-induced changes.Different conceptual models have been proposed to explain the nonideal cholesterol-lipid interactio...

Recent experimental results revealed that lipid-mediated interactions due to hydrophobic forces may be important in determining the protein topology after insertion in the membrane, in regulating the protein activity, in protein aggregation and in signal transduction. To gain insight into the lipid-mediated interactions between two intrinsic membrane proteins, we developed a mesoscopic model of a lipid bilayer with embedded proteins, which we studied with dissipative particle dynamics. Our calculations of the potential of mean force between transmembrane proteins show that hydrophobic forces drive long-range protein-protein interactions and that the nature of these interactions depends on the length of the protein hydrophobic segment, on the three-dimensional structure of the protein and on the properties of the lipid bilayer. To understand the nature of the computed potentials of mean force, the concept of hydrophilic shielding is introduced. The observed protein interactions are interpreted as resulting from the dynamic reorganization of the system to maintain an optimal hydrophilic shielding of the protein and lipid hydrophobic parts, within the constraint of the flexibility of the components. Our results could lead to a better understanding of several membrane processes in which protein interactions are involved.

We study the phase behavior of saturated lipids as a function of temperature and tail length for two coarse-grained models: the soft-repulsive model typically employed with dissipative particle dynamics (DPD) and the MARTINI model. We characterize the simulated transitions through changes in structural properties, and we introduce a computational method to monitor changes in enthalpy, as is done experimentally with differential scanning calorimetry. The lipid system experimentally presents four different bilayer phasessubgel, gel, ripple, and fluidand the DPD model describes all of these phases structurally while MARTINI describes a single orderÀdisorder transition between the gel and the fluid phases. Given both models' varying degrees of success in displaying accurate structural and thermodynamic signatures, there is an overall satisfying extent of agreement for the coarse-grained models. We also study the lipid dynamics displayed by these models for the various phases, discussing this dynamics with relation to fidelity to experiment and computational efficiency.

In this paper, we present a coarse-grained model of a hydrated saturated phospholipid bilayer (dimyristoylphosphatidylcholine, DMPC) containing cholesterol that we study using a hybrid dissipative particle dynamics-Monte Carlo method. This approach allows us to reach the time and length scales necessary to study structural and mechanical properties of the bilayer at various temperatures and cholesterol concentrations. The properties studied are the area per lipid, condensation, bilayer thickness, tail order parameters, bending modulus, and area compressibility. Our model quantitatively reproduces most of the experimental effects of cholesterol on these properties and reproduces the main features of the experimental phase and structure diagrams. We also present all-atom simulation results of the system and use these results to further validate the structure of our coarse-grained bilayer. On the basis of the changes in structural properties, we propose a temperature-composition structure diagram, which we compare with the experimental phase and structure diagrams. Attention is paid to the reliability and interpretation of the model and simulation method and of the different experimental techniques. The lateral organization of cholesterol in the bilayer is discussed.