Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations
Molecular Mechanism of Allosteric Communication in Hsp70 Revealed by Molecular Dynamics Simulations
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DOI：
10.1371/journal.pcbi.1002844
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发表时间：
2012-12-01
影响因子：
4.3
通讯作者：
Morra, Giulia
中科院分区：
文献类型：
--
作者：
Chiappori, Federica;Merelli, Ivan;Morra, Giulia
研究配体调控的蛋白质结构域之间的变构偶联是理解细胞生命调控的基础。分子伴侣的Hsp 70家族代表其中核苷酸结合结构域（NBD）处的ATP结合和水解调节底物结合结构域（SBD）处的底物识别的蛋白质的实例。在此，通过分子动力学模拟，从不同的构象和配体状态开始，对Hsp 70家族的变构（Hsp 70-DnaK）和非变构结构同源物（Hsp 110-Sse 1）进行比较分析。内部波动和局部变形模式的配体依赖性调制的分析突出了ATP-ADP交换后在残基水平上发生的结构和动力学变化，这些变化与封闭结构和开放结构之间的构象转变有关。通过识别动态响应的蛋白质区域和特定的跨结构域氢键模式，区分Hsp 70从Hsp 110作为一个功能的核苷酸，我们提出了一个变构信号传播的ATP编码的构象信号的分子机制。
Investigating ligand-regulated allosteric coupling between protein domains is fundamental to understand cell-life regulation. The Hsp70 family of chaperones represents an example of proteins in which ATP binding and hydrolysis at the Nucleotide Binding Domain (NBD) modulate substrate recognition at the Substrate Binding Domain (SBD). Herein, a comparative analysis of an allosteric (Hsp70-DnaK) and a non-allosteric structural homolog (Hsp110-Sse1) of the Hsp70 family is carried out through molecular dynamics simulations, starting from different conformations and ligand-states. Analysis of ligand-dependent modulation of internal fluctuations and local deformation patterns highlights the structural and dynamical changes occurring at residue level upon ATP-ADP exchange, which are connected to the conformational transition between closed and open structures. By identifying the dynamically responsive protein regions and specific cross-domain hydrogen-bonding patterns that differentiate Hsp70 from Hsp110 as a function of the nucleotide, we propose a molecular mechanism for the allosteric signal propagation of the ATP-encoded conformational signal.