A model of lipid-free apolipoprotein A-I revealed by iterative molecular dynamics simulation

PloS One
Xing ZhangShengli Zhang

Abstract

Apolipoprotein A-I (apo A-I), the major protein component of high-density lipoprotein, has been proven inversely correlated to cardiovascular risk in past decades. The lipid-free state of apo A-I is the initial stage which binds to lipids forming high-density lipoprotein. Molecular models of lipid-free apo A-I have been reported by methods like X-ray crystallography and chemical cross-linking/mass spectrometry (CCL/MS). Through structural analysis we found that those current models had limited consistency with other experimental results, such as those from hydrogen exchange with mass spectrometry. Through molecular dynamics simulations, we also found those models could not reach a stable equilibrium state. Therefore, by integrating various experimental results, we proposed a new structural model for lipid-free apo A-I, which contains a bundled four-helix N-terminal domain (1-192) that forms a variable hydrophobic groove and a mobile short hairpin C-terminal domain (193-243). This model exhibits an equilibrium state through molecular dynamics simulation and is consistent with most of the experimental results known from CCL/MS on lysine pairs, fluorescence resonance energy transfer and hydrogen exchange. This solution-state lipid...Continue Reading

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Citations

Nov 14, 2017·Nature Structural & Molecular Biology·John T MelchiorW Sean Davidson
Jul 26, 2017·Molecular Plant Pathology·Jeannette RapicavoliCaroline Roper
Sep 27, 2018·The Journal of Physical Chemistry Letters·Arjun RayLipi Thukral

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Methods Mentioned

BETA
X-ray
fluorescence studies
circular dichroism
electron paramagnetic resonance
NMR
nuclear magnetic resonance
FRET

Software Mentioned

HDX
SASA
VMD solvate
Chimera
MS
Modeller9
CHARMM22
VMD
NAMD2

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