Structural features and dynamics properties of human apolipoprotein A-I in a model of synthetic HDL

High-density lipoproteins (HDL) play a major role in the reverse transport of cholesterol and have antiatherogenic activities. Their major protein component is apolipoprotein (apo) A-I. While apoA-I amphipathic α-helix based secondary structure has been extensively investigated, for its lipid-bound tertiary structure only theoretical models have been proposed. In the past years, experimental approaches aimed at a direct visualization of HDL structure have been exploited, but data obtained through different microscopy techniques are conflicting and do not settle the issue. Here we present a 50 ns molecular dynamics simulation of a synthetic HDL containing two molecules of apoA-I and 101 of l-α-palmitoyl-oleoyl-phosphatidylcholine. Essential dynamics and structural property investigations suggest that the stabilization of the system is obtained through specific motions, whose driving forces are protein-phospholipid interactions. The most important are: the relative sliding of the two apoA-I molecules along their major axes, the relative rotation of the protein chains, and the out-of-plane deformation around proline hinges. The sliding and the out-of-plane deformation allow apoA-I to optimize its interactions with phospholipids, while the rotation is useful to maximize protein-protein salt bridges. The correspondence between computed parameters and their experimental counterparts contributes to validate our model and its dynamic behaviors. Our findings help in defining a molecular model for apoA-I contained in HDL and suggest a possible mechanism through which apoA-I can vary its diameter and accommodate different numbers of phospholipids during the metabolism of HDL.