Characterization Of Apolipoprotein Mimetic Peptides On Nascent High Density Lipoproteins

A nascent high-density lipoprotein (HDL) is a discoidal bilayer composed of phospholipids, cholesterols, and two apolipoproteins that form a scaffold that stabilizes the assembly. Apolipoprotein mimetic peptides are short synthetic peptides that share features of apolipoproteins and have potential therapeutic value based on their ability to form and stabilize nascent HDL. A key question in designing mimetic peptides is why some are more efficient than others. We characterize the properties of four mimetic peptides rich in the amino acids E, L, and K (called ELK peptides), using a combination of Molecular Dynamics simulations and experimental techniques. Experiments show that the hydrophobic and neutral ELKs have a significantly higher ability to form nascent HDLs than the positive or negative peptides. An in silico model of a discoidal bilayer was developed by introducing a water slab perpendicular to the bilayer head group surface, leading to acyl chains of edges exposed to water. Simulations on this model discoidal bilayer with peptides indicate that hydrophobic and neutral ELKs stabilize the assembly by forming scaffolds at the edges in a picket fence arrangement; the adjacent peptides are held together by strong salt-bridges. In contrast, the positive and negative ELKs diffuse to the head group surface, do not form effective scaffolds, and fail to stabilize the discoidal assembly. Hence, the simulations provide a structural rational for the experimental observations, and provide an avenue for computer based design of apolipoprotein mimetic peptides.