Structural properties of apolipoprotein A-I mimetic peptides that promote ABCA1-dependent cholesterol efflux

• Main Authors: Rafique M. Islam, Mohsen Pourmousa, Denis Sviridov, Scott M. Gordon, Edward B. Neufeld, Lita A. Freeman, B. Scott Perrin, Richard W. Pastor, Alan T. Remaley
• Format: Article
• Language: English
• Published: Nature Publishing Group 2018-02-01
• Series: Scientific Reports
• Online Access: https://doi.org/10.1038/s41598-018-20965-2

Abstract Peptides mimicking the major protein of highdensity lipoprotein (HDL), apolipoprotein A-I (apoA-I), are promising therapeutics for cardiovascular diseases. Similar to apoA-I, their atheroprotective property is attributed to their ability to form discoidal HDL-like particles by extracting cellular cholesterol and phospholipids from lipid microdomains created by the ABCA1 transporter in a process called cholesterol efflux. The structural features of peptides that enable cholesterol efflux are not well understood. Herein, four synthetic amphipathic peptides denoted ELK, which only contain Glu, Leu, Lys, and sometimes Ala, and which have a wide range of net charges and hydrophobicities, were examined for cholesterol efflux. Experiments show that ELKs with a net neutral charge and a hydrophobic face that subtends an angle of at least 140° are optimal for cholesterol efflux. All-atom molecular dynamics simulations show that peptides that are effective in promoting cholesterol efflux stabilize HDL nanodiscs formed by these peptides by the orderly covering of the hydrophobic acyl chains on the edge of the disc. In contrast to apoA-I, which forms an anti-parallel double belt around the HDL, active peptides assemble in a mostly anti-parallel “picket fence” arrangement. These results shed light on the efflux ability of apoA-I mimetics and inform the future design of such therapeutics.