IN SILICO STUDIES ON MODELS OF SYNTHETIC HDL

The major protein components of high-density lipoproteins (HDL) are apolipoprotein (apo) A-I and apoA-II. Sixty-three different mutations of apoA-I are known. Among them, apoA-IMilano (IM) and apoA-IParis (IP) are characterized by an R-C substitution, leading to the formation of disulfide-linked homodimers and of heterodimers with apoA-II. From observations in humans and in animal models apoA-IM and apoA-IP behave as molecules with an intrinsic antiatherogenic activity. No experimental structure at atomic resolution of lipid-bound apoA-I is available. In this thesis I present four molecular models of synthetic HDL containing a lipidic core of palmitoyloleoyl- phosphatidylcholine and either two molecules of wild type apoA-I, or one apoA-IM homodimer, or one apoA-IP homodimer, or two molecules of apoA-IM–apoA-II heterodimer. On all the systems I computed molecular dynamics simulations to obtain reliable data about the behavior of apoA-I in a lipidic environment and to sharpen the understanding of its molecular functions in regulating cholesterol homeostasis. In all the four models of s- HDL the increase with time in the number of favorable interactions between apoA-I and phospholipids was the driving force for the structural reorganization and stabilization of s-HDL. I found a strong correspondence between computed and experimental properties, which supports the reliability of my results.