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首页> 外文期刊>Biochemistry >An Experimentally Robust Model of Monomeric Apolipoprotein A-I Created from a Chimera of Two X-ray Structures and Molecular Dynamics Simulations
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An Experimentally Robust Model of Monomeric Apolipoprotein A-I Created from a Chimera of Two X-ray Structures and Molecular Dynamics Simulations

机译：从两个X射线结构的嵌合体创建的单体载脂蛋白A-I的实验鲁棒模型和分子动力学模拟

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摘要

High-density lipoprotein (HDL) retards atherosclerosis by accepting cholesterol from the artery wall. However, the structure of the proposed acceptor, monomeric apolipoprotein A-I (apoA-I), the major protein of HDL, is poorly understood. Two published models for monomeric apoA-I used cross-linking distance constraints to derive best fit conformations. This approach has limitations. (i) Cross-linked peptides provide no information about secondary structure. (ii) A protein chain can be folded in multiple ways to create a best fit. (iii) Ad hoc folding of a secondary structure is unlikely to produce a stable orientation of hydrophobic and hydrophilic residues. To address these limitations, we used a different approach. We first noted that the dimeric apoA-I crystal structure, (Delta 185-243)apoA-I, is topologically identical to a monomer in which helix 5 forms a helical hairpin, a monomer with a hydrophobic cleft running the length of the molecule. We then realized that a second crystal structure, (Delta 1-43)apoA-I, contains a C-terminal structure that fits snuggly via aromatic and hydrophobic interactions into the hydrophobic cleft. Consequently, we combined these crystal structures into an initial model that was subjected to molecular dynamics simulations. We tested the initial and simulated models and the two previously published models in three ways: against two published data sets (domains predicted to be helical by H/D exchange and six spin-coupled residues) and against our own experimentally determined cross-linking distance constraints. We note that the best fit simulation model, superior by all tests to previously published models, has dynamic features of a molten globule with interesting implications for the functions of apoA-I.
机译：高密度脂蛋白（HDL）通过接受来自动脉壁的胆固醇来延缓动脉粥样硬化。然而，对所提出的受体，即载脂蛋白A-I（apoA-I）（HDL的主要蛋白）的结构了解甚少。两个公开的单体载脂蛋白A-I模型使用交联距离约束来推导最佳拟合构象。这种方法有局限性。 （i）交联的肽不提供有关二级结构的信息。 （ii）蛋白质链可以以多种方式折叠以形成最佳匹配。 （iii）二级结构的临时折叠不太可能产生疏水和亲水残基的稳定取向。为了解决这些限制，我们使用了另一种方法。我们首先注意到，二聚体apoA-I晶体结构（Delta 185-243）apoA-I在拓扑上与其中螺旋5形成螺旋发夹的单体在拓扑上相同，该单体具有在分子的长度上延伸的疏水性裂缝。然后，我们意识到第二个晶体结构（Delta 1-43）apoA-I包含一个C端结构，该结构通过芳香族和疏水性相互作用紧密地配合在疏水缝隙中。因此，我们将这些晶体结构组合成一个初始模型，并对该模型进行了分子动力学模拟。我们以三种方式测试了初始模型和模拟模型以及两个先前发布的模型：针对两个发布的数据集（通过H / D交换预测为螺旋形的域和六个自旋耦合的残基）以及针对我们自己实验确定的交联距离约束。我们注意到，最适合的仿真模型（在所有测试中均优于先前发布的模型）具有熔融小球的动态特征，对apoA-I的功能具有有趣的意义。

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