title: Validation of previous computer models and MD simulations of discoidal HDL by a recent crystal structure of apoA-I.
abstract: HDL is a population of apoA-I-containing particles inversely correlated with heart disease. Because HDL is a soft form of matter deformable by thermal fluctuations, structure determination has been difficult. Here, we compare the recently published crystal structure of lipid-free (Δ185-243)apoA-I with apoA-I structure from models and molecular dynamics (MD) simulations of discoidal HDL. These analyses validate four of our previous structural findings for apoA-I: i) a baseline double belt diameter of 105 Å ii) central α helixes with an 11/3 pitch; iii) a "presentation tunnel" gap between pairwise helix 5 repeats hypothesized to move acyl chains and unesterified cholesterol from the lipid bilayer to the active sites of LCAT; and iv) interchain salt bridges hypothesized to stabilize the LL5/5 chain registry. These analyses are also consistent with our finding that multiple salt bridge-forming residues in the N-terminus of apoA-I render that conserved domain "sticky." Additionally, our crystal MD comparisons led to two new hypotheses: i) the interchain leucine-zippers previously reported between the pair-wise helix 5 repeats drive lipid-free apoA-I registration; ii) lipidation induces rotations of helix 5 to allow formation of interchain salt bridges, creating the LCAT presentation tunnel and "zip-locking" apoA-I into its full LL5/5 registration.
authors: Department of Medicine, Atherosclerosis Research Unit, and Center for Computational and Structural Dynamics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. segrest@uab.edu
authors: Jere P
authors: JP
authors: Segrest
authors: Martin K
authors: MK
authors: Jones
authors: Andrea
authors: A
authors: Catte
authors: Saravana P
authors: SP
authors: Thirumuruganandham
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008074:Lipoproteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055672:Static Electricity
chemical_list: D016632:Apolipoprotein A-I; D008074:Lipoproteins; C034366:discoidal lipoproteins