Probing the structure and dynamics of caveolin-1 in a caveolae-mimicking asymmetric lipid bilayer model.

Caveolin-1 is the principle membrane protein of caveolae and plays an important role in various cellular processes. The protein contains two helices (H1 and H2) connected by a three-residue break. Although caveolin-1 is assumed to adopt a U-shaped conformation in the transmembrane domain, with both the N-terminus and C-terminus exposed to the cytoplasm, the structure and dynamics of caveolin-1 in membranes are still unclear. Here, we performed six molecular dynamics simulations to characterize the structure and dynamics of caveolin-1 (residues D82-S136; Cav182-136) in a caveolae-mimicking asymmetric lipid bilayer. The simulations reveal that the structure of the caveolin scaffolding domain of caveolin-1 is dynamic, as it could be either fully helical or partly unstructured. Cav182-136 inserts into the inner leaflet of the asymmetric lipid bilayer with a stable U-shaped conformation and orients almost vertical to the bilayer surface. The simulations also provide new insights into the effects of caveolin-1 on the morphology of caveolae and the possible interacting site of cholesterol on caveolin-1.

Effects of ion interactions with a cholesterol-rich bilayer.

Previous molecular dynamics (MD) simulations of ion-lipid interactions have focused on pure phospholipid bilayers. Many functional microdomains in membranes have a complex composition of cholesterol and phospholipids. Here, we reveal the distinctiveness of the interactions and the effects of the ions on a cholesterol-rich bilayer by performing MD simulations of a cholesterol-rich bilayer with a Na(+)/K(+) mixture or a Na(+)/K(+)/Ca(2+)/Mg(2+) mixture. The simulations reveal that Ca(2+) maintains its dominant role in the interaction with the cholesterol-rich bilayer, but the binding affinity of Mg(2+) to the cholesterol-rich bilayer is even weaker than the affinities of Na(+) and K(+), whereas its interaction with pure phospholipid bilayers is strong and is only slightly weaker than that of Ca(2+). Additionally, it was found that the presence of additional divalent cations induces the headgroups of phospholipids to be more perpendicular to the membrane surface, reducing the lateral movement of lipids and slightly altering the ordering and packing of the cholesterol-rich bilayer, different from divalent cations, which strongly influence that ordering and packing of pure phospholipid bilayers. Therefore, this study indicates that cholesterol in the membrane could affect the interactions between membrane and cations. The findings could be helpful in understanding the biological processes relevant to regulation of cations in cholesterol-rich regions.