Molecular dynamics simulation of the Escherichia coli NikR protein:: Equilibrium conformational fluctuations reveal interdomain allosteric communication pathways
Molecular dynamics simulation of the Escherichia coli NikR protein:: Equilibrium conformational fluctuations reveal interdomain allosteric communication pathways
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DOI：
10.1016/j.jmb.2008.03.010
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发表时间：
2008-05-16
影响因子：
5.6
通讯作者：
Baker, Nathan A.
中科院分区：
文献类型：
--
作者：
Bradley, Michael J.;Chivers, Peter T.;Baker, Nathan A.
大肠杆菌 NikR 是一种同四聚体 Ni2+- 和 DNA 结合蛋白，可作为 NikABCDE 镍通透酶的转录抑制因子。该蛋白质由两个不同的结构域组成。每条链的 N 端 50 个氨基酸形成二聚体带-螺旋-螺旋 (RHH) 结构域的一部分，这是一种经过充分研究的 DNA 结合折叠。 83 个残基的 C 端镍结合结构域形成 ACT（天冬氨酸激酶、分支酸变位酶和 TyrA）折叠并包含四聚体界面。在本研究中，我们利用平衡分子动力学模拟来探索 NikR 四聚体的构象动力学，并确定 RHH 和 ACT 结构域内部和之间的重要残基相互作用，以深入了解 Ni2+ 对 DNA 结合活性的影响。使用基于原子位置波动和非共价接触的两种不同的相关性测量以及聚类算法来分析分子模拟数据，以定义两种类型的相关性测量具有相似相关模式的残基组。基于这些分析，我们定义了一系列残基相互关系，描述了 Ni2+- 和 DNA 结合位点之间的变构通讯途径，这些位点相距 40 A。我们的分析确定的几个残基先前已通过实验证明对 NikR 功能很重要。已识别残基的另一个子集在结构上连接了实验涉及的残基，并且可能有助于协调 ACT 和 RHH 结构域之间的变构通讯。 (C) 2008 Elsevier Ltd. 保留所有权利。
Escherichia coli NikR is a homotetrameric Ni2+- and DNA-binding protein that functions as a transcriptional repressor of the NikABCDE nickel permease. The protein is composed of two distinct domains. The N-terminal 50 amino acids of each chain forms part of the dimeric ribbon-helix-helix (RHH) domains, a well-studied DNA-binding fold. The 83-residue C-terminal nickel-binding domain forms an ACT (aspartokinase, chorismate mutase, and TyrA) fold and contains the tetrameric interface. In this study, we have utilized an equilibrium molecular dynamics simulation in order to explore the conformational dynamics of the NikR tetramer and determine important residue interactions within and between the RHH and ACT domains to gain insight into the effects of Ni2+ on DNA-binding activity. The molecular simulation data were analyzed using two different correlation measures based on fluctuations in atomic position and noncovalent contacts together with a clustering algorithm to define groups of residues with similar correlation patterns for both types of correlation measure. Based on these analyses, we have defined a series of residue interrelationships that describe an allosteric communication pathway between the Ni2+- and DNA-binding sites, which are separated by 40 A. Several of the residues identified by our analyses have been previously shown experimentally to be important for NikR function. An additional subset of the identified residues structurally connects the experimentally implicated residues and may help coordinate the allosteric communication between the ACT and RHH domains. (C) 2008 Elsevier Ltd. All rights reserved.