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标题：Validation of previous computer models and MD simulations of discoidal HDL by a recent crystal structure of apoA-I
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作者：Jere P. Segrest ; Martin K. Jones ; Andrea Catte 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2012
卷号：53
期号：9
页码：1851-1863
DOI：10.1194/jlr.M026229
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：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.
关键词：apolipoprotein A-I ; all-atom simulation ; Molecular Dynamics ; X-ray crystallography ; α11/3 helix