Minimum free energy path of ligand-induced transition in adenylate kinase.
Minimum free energy path of ligand-induced transition in adenylate kinase.
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DOI：
10.1371/journal.pcbi.1002555
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发表时间：
2012
影响因子：
4.3
通讯作者：
Kidera A
中科院分区：
文献类型：
--
作者：
Matsunaga Y;Fujisaki H;Terada T;Furuta T;Moritsugu K;Kidera A
蛋白质的大规模构象变化涉及高维空间复杂自由能表面上的跨垒跃迁。这种罕见的事件不能有效地捕捉到传统的分子动力学模拟。在这里，我们表明，通过结合在飞弦方法和多状态班尼特接受比（MBAR）的方法，自由能分布的构象转变途径在大肠杆菌腺苷酸激酶可以在一个高维空间的特点。在由20个最大振幅的主模所构成的20维空间中，采用动态弦方法探索了腺苷酸激酶构象转变的最小自由能路径，并用MBAR方法成功地计算了路径上的自由能和各种沿着平均物理量.配体结合对途径的影响，其特征在于在盖形ATP结合域（LID）和AMP结合域（AMPbd）的刚体运动。发现LID结构域能够在没有配体的情况下部分闭合，而AMPbd结构域的闭合需要配体结合。配体结合形式的过渡态系综被确定为特征在于配体与AMPbd结构域的高度特异性结合的那些结构，并且通过无限制的MD模拟进行验证。还发现LID结构域的完全闭合需要P环周围的溶剂脱水。这些发现表明，两种不同类型的结构域运动的相互作用是在酶的构象转变的一个重要特征。蛋白质的构象转变在蛋白质的催化、变构调节和信号转导等功能中起着重要作用。其中，酶催化和动力学之间的关系已特别充分的研究。本研究中的靶分子，来自大肠杆菌的腺苷酸激酶，以允许其底物（ATP和AMP）结合的开放状态和发生催化反应的封闭状态存在。在这个分子模拟研究中，我们已经阐明了开放和封闭状态之间的构象转变的原子细节。结合使用的路径搜索方法和自由能计算方法，使过渡途径被跟踪原子的细节上微米到毫秒的时间尺度。我们的模拟表明，两个配体分子，AMP和ATP，在过渡的情况下发挥独特的作用。AMP与铰链区的特异性结合首先发生，并在过渡中产生瓶颈。ATP结合，这需要一个封闭的水分子的脱水，是在过渡的后期完成。
Large-scale conformational changes in proteins involve barrier-crossing transitions on the complex free energy surfaces of high-dimensional space. Such rare events cannot be efficiently captured by conventional molecular dynamics simulations. Here we show that, by combining the on-the-fly string method and the multi-state Bennett acceptance ratio (MBAR) method, the free energy profile of a conformational transition pathway in Escherichia coli adenylate kinase can be characterized in a high-dimensional space. The minimum free energy paths of the conformational transitions in adenylate kinase were explored by the on-the-fly string method in 20-dimensional space spanned by the 20 largest-amplitude principal modes, and the free energy and various kinds of average physical quantities along the pathways were successfully evaluated by the MBAR method. The influence of ligand binding on the pathways was characterized in terms of rigid-body motions of the lid-shaped ATP-binding domain (LID) and the AMP-binding (AMPbd) domains. It was found that the LID domain was able to partially close without the ligand, while the closure of the AMPbd domain required the ligand binding. The transition state ensemble of the ligand bound form was identified as those structures characterized by highly specific binding of the ligand to the AMPbd domain, and was validated by unrestrained MD simulations. It was also found that complete closure of the LID domain required the dehydration of solvents around the P-loop. These findings suggest that the interplay of the two different types of domain motion is an essential feature in the conformational transition of the enzyme. Conformational transitions of proteins have been postulated to play a central role in various protein functions such as catalysis, allosteric regulation, and signal transduction. Among these, the relation between enzymatic catalysis and dynamics has been particularly well-studied. The target molecule in this study, adenylate kinase from Escherichia coli, exists in an open state which allows binding of its substrates (ATP and AMP), and a closed state in which catalytic reaction occurs. In this molecular simulation study, we have elucidated the atomic details of the conformational transition between the open and the closed states. A combined use of the path search method and the free energy calculation method enabled the transition pathways to be traced in atomic detail on micro- to millisecond time scales. Our simulations revealed that two ligand molecules, AMP and ATP, play a distinctive role in the transition scenario. The specific binding of AMP into the hinge region occurs first and creates a bottleneck in the transition. ATP-binding, which requires the dehydration of an occluded water molecule, is completed at a later stage of the transition.
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影响因子：
3.3
作者：
Cukier, Robert I.
通讯作者：
Cukier, Robert I.
影响因子：
56.9
作者：
FRAUENFELDER, H;SLIGAR, SG;WOLYNES, PG
通讯作者：
WOLYNES, PG
影响因子：
3
作者：
Duan, Y;Wu, C;Kollman, P
通讯作者：
Kollman, P
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1073/pnas.0708600104
发表时间：
2007-11-13
影响因子：
11.1
作者：
Hanson, Jeffrey A.;Duderstadt, Karl;Yang, Haw
通讯作者：
Yang, Haw