| In this work we use molecular simulations to investigate how cholesterol affects membrane-mediated protein-protein interactions. We consider a typical hydrated biological model membrane containing saturated phospholipids (for example, dimyristoylphosphatidylcholine or DMPC), cholesterol, and trans-membrane proteins. We introduce a model in which the different molecules are coarse-grained, retaining their hydrophobic and hydrophilic properties together with their main structure and flexibility. The system is studied using a hybrid Monte-Carlo dissipative particle dynamics method.;First we study lipid-mediated protein-protein interactions in a pure hydrated saturated phospholipid bilayer. The potential of mean force between the proteins show that hydrophobic forces drive long-range lipid-mediated 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. The concept of hydrophilic shielding is introduced to gain insight into the nature of the computed potentials of mean force.;To study the effect of cholesterol on the properties of a membrane, we extend our model to cholesterol. Structural and mechanical properties of the hydrated bilayer containing a saturated lipid and cholesterol are studied 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. The model quantitatively reproduces most of the experimental effects of cholesterol on these properties and reproduces the main features of the experimental temperature-composition phase diagram. Based on the changes in structural properties a temperature-composition structure diagram is proposed, which is compared with the experimental phase and structure diagrams. The lateral organization of cholesterol in the bilayer is also discussed. In a second part, modifications of the cholesterol model are made to allow a better understanding of the cholesterol condensation effect. This condensation effect is further discussed in relation to the DMPC-cholesterol phase behavior.;Finally, the effect of cholesterol on lipid-mediated protein-protein interactions is investigated. This is done in accordance with the results concerning the effect of cholesterol on the phase behavior of lipid bilayers. The calculations of the potential of mean force between proteins and protein clusters show that the addition of cholesterol gradually reduces repulsive lipid-mediated interactions between certain proteins. At a given cholesterol concentration, the interactions even become attractive. Hence, cholesterol significantly promotes protein aggregation. The role of protein-induced dynamical cholesterol-enriched and cholesterol-depleted shells in these effects is discussed in detail. |
