Zhang Xing, Lei Dongsheng, Zhang Lei, Rames Matthew, Zhang Shengli
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.
Molecular Foundry, Materials Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
PLoS One. 2015 Mar 20;10(3):e0120233. doi: 10.1371/journal.pone.0120233. eCollection 2015.
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.
载脂蛋白A-I（apo A-I）是高密度脂蛋白的主要蛋白质成分，在过去几十年中已被证明与心血管风险呈负相关。apo A-I的无脂状态是其与脂质结合形成高密度脂蛋白的初始阶段。已通过X射线晶体学和化学交联/质谱（CCL/MS）等方法报道了无脂apo A-I的分子模型。通过结构分析，我们发现当前的这些模型与其他实验结果（如质谱氢交换实验结果）的一致性有限。通过分子动力学模拟，我们还发现这些模型无法达到稳定的平衡状态。因此，通过整合各种实验结果，我们提出了一种新的无脂apo A-I结构模型，该模型包含一个成束的四螺旋N端结构域（1-192），其形成一个可变的疏水凹槽和一个可移动的短发夹C端结构域（193-243）。该模型通过分子动力学模拟呈现出平衡状态，并且与CCL/MS在赖氨酸对、荧光共振能量转移和氢交换方面已知的大多数实验结果一致。这种溶液状态的无脂apo A-I模型可能有助于阐明apo A-I在高密度脂蛋白形成过程中与脂质结合时可能的构象转变。
