Molecular Dynamics Simulations of Apolipoprotein A-I Peptide Mimetic 4F

Abstract

Coronary heart disease is the leading cause of death in the United States, claiming more lives than the next seven leading causes of death combined. High levels of high density lipoprotein (HDL) have been correlated with lower rates of coronary heart disease. Apolipoprotein A-I (apoA-I), is the principle protein in HDL, is a 243-residue class A amphipathic alpha helix capable of binding a variable number of lipid molecules. ApoA-I mimetic peptides synthesized by Anantharamaiah et al. are 18-residue class A amphipathic helices. Although they have no sequence homology to apoA-I, the peptides bind to lipids in a manner similar to that of apoA-I (i.e. antiparallel double-belt on the edge of the lipid disc). Molecular dynamics simulations of the lipid-bound peptide mimetic 4F were performed for 30 ns in explicit water using CHARMM22/27 parameters. The peptides were arranged in a stacked and staggered conformation to determine if there was any difference in the stability of the belt structure of the peptides. In the initial model, 16 straight alpha-helical chains of 4F were placed around two leaflets of 108 dimyristoylphosphatidylcholines (DMPC). In both simulations all peptides remain in contact with the lipid. The staggered model gives a more circular shape while the stacked model distorts into an oval shape. The staggered model also has a lower conformational energy than the stacked model, indicating that peptide-lipid complexes in which the peptides are staggered may be the more stable form. Salt bridge analysis shows there are three additional salt bridge interactions formed that are not present in the stacked conformation. These interactions may be a contributing factor for the more stable form of the staggered conformation.