title: Thermal stability of apolipoprotein A-I in high-density lipoproteins by molecular dynamics.
abstract: Apolipoprotein (apo) A-I is an unusually flexible protein whose lipid-associated structure is poorly understood. Thermal denaturation, which is used to measure the global helix stability of high-density lipoprotein (HDL)-associated apoA-I, provides no information about local helix stability. Here we report the use of temperature jump molecular dynamics (MD) simulations to scan the per-residue helix stability of apoA-I in phospholipid-rich HDL. When three 20 ns MD simulations were performed at 500 K on each of two particles created by MD simulations at 310 K, bilayers remained intact but expanded by 40%, and total apoA-I helicity decreased from 95% to 72%. Of significance, the conformations of the overlapping N- and C-terminal domains of apoA-I in the particles were unusually mobile, exposing hydrocarbon regions of the phospholipid to solvent; a lack of buried interhelical salt bridges in the terminal domains correlated with increased mobility. Nondenaturing gradient gels show that 40% expansion of the phospholipid surface of 100:2 particles by addition of palmitoyloleoylphosphatidylcholine exceeds the threshold of particle stability. As a unifying hypothesis, we propose that the terminal domains of apoA-I are phospholipid concentration-sensitive molecular triggers for fusion/remodeling of HDL particles. Since HDL remodeling is necessary for cholesterol transport, our model for remodeling has substantial biomedical implications.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Jones
authors.forename: Andrea
authors.initials: A
authors.lastname: Catte
authors.forename: James C
authors.initials: JC
authors.lastname: Patterson
authors.forename: Feifei
authors.initials: F
authors.lastname: Gu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D008051:Lipid Bilayers; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008954:Models, Biological; D008958:Models, Molecular; D010713:Phosphatidylcholines / Q000378:metabolism; D011489:Protein Denaturation; D017510:Protein Folding; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D013696:Temperature
chemical_list: D016632:Apolipoprotein A-I; D008051:Lipid Bilayers; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; C028694:1-palmitoyl-2-oleoylphosphatidylcholine