title: A model of lipid-free apolipoprotein A-I revealed by iterative molecular dynamics simulation.
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-free apo A-I model may elucidate the possible conformational transitions of apo A-I binding with lipids in high-density lipoprotein formation.
authors: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China; Molecular Foundry, Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors: Xing
authors: X
authors: Zhang
authors: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China; Molecular Foundry, Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors: Dongsheng
authors: D
authors: Lei
authors: Molecular Foundry, Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors: Lei
authors: L
authors: Zhang
authors: Molecular Foundry, Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors: Matthew
authors: M
authors: Rames
authors: Department of Applied Physics, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China.
authors: Shengli
authors: S
authors: Zhang
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry*; D003432:Cross-Linking Reagents; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D013058:Mass Spectrometry; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D003432:Cross-Linking Reagents; D008055:Lipids