Novel Insights to the Design of Apolipoprotein AI Mimetic Peptides

Abstract

Peptides mimicking the major protein of high-density lipoprotein, apolipoprotein AI (APOA1), are promising therapeutics for cardiovascular diseases because they impede the development of atherosclerotic lesions. Similar to APOA1, their atheroprotective characteristic is attributed to the ability to form discoidal bilayer when lipid transporters pleat lipids and cholesterols from macrophages, a process called cholesterol efflux. Understanding the structure of nanodiscs generated by APOA1 mimetics is crucial to the rational design of such therapeutics. However, high-density lipoproteins are resistant to traditional high-resolution approaches, such as NMR or X-ray crystallography. Herein, all-atom Molecular Dynamics simulations on Anton-2 supercomputer determine the structure of nanodiscs and contrast behaviors of two peptides that were experimentally shown to be potent and inactive in cholesterol efflux. The peptides are α-helical, amphipathic, have 18 residues, and solely contain Glu, Leu, and Lys. A 3-μs simulation of a nanodisc with potent peptides shows that they migrate from the disc surface to the edge to cover acyl chains of lipids. In contrast to APOA1 which takes a “belt” configuration, the peptides form a “picket-fence” arrangement whereby they orient along the disc normal. Each peptide interacts with its two neighbors through Lys-Glu salt-bridges mostly in an antiparallel fashion, hence a peptide oligomer. A 2-μs simulation of a nanodisc with inactive peptides, in contrast, demonstrates their incapability to stabilize nanodiscs. Starting from an ideal antiparallel picket-fence on the disc edge, the peptides dimerize but dimers migrate from the edge to the surface leaving acyl chains exposed to water. This is due to the repulsion of negatively charged sidechains of adjacent dimers. Therefore, the simulations establish that APOA1 mimetics should oligomerize to effectively promote cholesterol efflux and that their dimerization is necessary but not sufficient. This insight informs the future design of these peptides.