Apo Adenylate Kinase Encodes Its Holo Form: A Principal Component and Varimax Analysis
Apo Adenylate Kinase Encodes Its Holo Form: A Principal Component and Varimax Analysis
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DOI：
10.1021/jp8053795
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发表时间：
2009-02-12
影响因子：
3.3
通讯作者：
Cukier, Robert I.
中科院分区：
文献类型：
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作者：
Cukier, Robert I.
当腺苷酸激酶的载脂蛋白，开放形式关闭底物AMP和Mg(2+)-ATP时，其LID和AMP结合（AMPbd）结构域发生大规模运动。它可能是在载子状态下提供一系列构象的酶的一个例子，它的底物可以从中选择和结合产生催化能力强的构象。在这项工作中，用分子动力学方法获得了载脂蛋白大肠杆菌腺苷酸激酶（AKE）的波动。用主成分分析（PCA）对得到的轨迹进行分析，主成分分析将原子运动按其对总蛋白质波动的贡献递减顺序分解为正交模式。在apo AKE中，一小组PCA模态描述了大部分的波动。通过使用变大旋转方法，改进了对这些模式的重要贡献的原子运动的识别，该方法将PCA模式旋转到一个新的模式集，该模式集将原子贡献集中到这些新模式中的更小的原子集。通过这种方式，阐明了LID和AMPbd结构域重要运动的性质。主要的PCA模式用于研究载脂蛋白AKE是否可以波动到像全息一样的构象，即使载脂蛋白轨迹主要局限于初始载脂蛋白结构周围的区域。这是通过表达从全息和载脂蛋白晶体结构中获得的蛋白质坐标之间的差异来实现的，并使用载脂蛋白AKE轨迹的PCA模式作为基础。由一小组载脂蛋白PCA模式描述的相干运动被证明能够产生与蛋白质的全息构象非常相似的蛋白质构象。从这个意义上说，载脂蛋白AKE确实在其波动中编码了类全息构象的信息。
Adenylate kinase undergoes large-scale motions of its LID and AMP-binding (AMPbd) domains when its apo, open form closes over its substrates, AMP and Mg(2+)-ATP. It may be an example of an enzyme that provides an ensemble of conformations in its apo state from which its substrates can select and bind to produce catalytically competent conformations. In this work, the fluctuations of the enzyme apo Escherichia coli adenylate kinase (AKE) are obtained with molecular dynamics. The resulting trajectory is analyzed with principal component analysis (PCA) that decomposes the atom motions into orthogonal modes ordered by their decreasing contributions to the total protein fluctuation. In apo AKE, a small set of the PCA modes describes the bulk of the fluctuations. Identification of the atom motions that are important contributors to these modes is improved with the use of a varimax rotation method that rotates the PCA modes to a new mode set that concentrates the atom contributions to a smaller set of atoms in these new modes. In this way, the nature of the important motions of the LID and AMPbd domains are clarified. The dominant PCA modes are used to investigate if apo AKE can fluctuate to conformations that are holo-like, even though the apo trajectory is mainly confined to a region around the initial apo structure. This is accomplished by expressing the difference between the protein coordinates, obtained from the holo and apo crystal structures, using as a basis the PCA modes from the apo AKE trajectory. The coherent motion described by a small set of the apo PCA modes is shown to be able to produce protein conformations that are quite similar to the holo conformation of the protein. In this sense, apo AKE does encode in its fluctuations information about holo-like conformations.