Insights into MAPK p38α DFG flip mechanism by accelerated molecular dynamics
Insights into MAPK p38α DFG flip mechanism by accelerated molecular dynamics
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DOI：
10.1016/j.bmc.2010.07.047
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发表时间：
2010-09-15
影响因子：
3.5
通讯作者：
Menziani, M. Cristina
中科院分区：
文献类型：
--
作者：
Filomia, Federico;De Rienzo, Francesca;Menziani, M. Cristina
MAPK p38 α激活环起始处的DFG基序在结合变构II型和III型抑制剂后经历局部结构重组，这导致残基F-169从埋藏构象（定义为DFG-入）移动到溶剂暴露构象（定义为DFG-出）。尽管已经进行了实验和计算机模拟研究，目的是揭示DFG-in到DFG-out转变的细节，但分子机制仍远未被明确描述。加速分子动力学（AMD）技术已被应用于模拟p38 α的活性环柔性，并对仅在某些条件或时间段内可接近的特殊蛋白质构象进行采样。从实验已知的蛋白质的初始和最终状态的假设开始，该研究允许描述的相互作用网络和结构中间体，导致蛋白质改变其环构象和活性位点的可及性。除了几个重要的氢键相互作用，主要的作用似乎是由阳离子π相互作用，涉及DFG环残基F-169，参与稳定的中间构象，并在其随之而来的过渡到DFG出构象。从这项研究中，见解，这可能证明是有用的抑制剂设计和/或定点诱变研究。(C)2010爱思唯尔有限公司版权所有。
The DFG motif at the beginning of the activation loop of the MAPK p38 alpha undergoes a local structural reorganization upon binding of allosteric type-II and type-III inhibitors, which causes the residue F-169 to move from a buried conformation (defined as DFG-in) to a solvent exposed conformation (defined as DFG-out). Although both experimental and computer simulation studies had been performed with the aim of unveiling the details of the DFG-in to DFG-out transition, the molecular mechanism is still far from being unequivocally depicted.Here, the accelerated molecular dynamics (AMD) technique has been applied to model the active loop flexibility of p38 alpha and sample special protein conformations which can be accessible only in some conditions or time periods. Starting from the assumption of an experimentally known initial and final state of the protein, the study allowed the description of the interaction network and the structural intermediates which lead the protein to change its loop conformation and active site accessibility. Besides a few important hydrogen bond interactions, a primary role seems to be played by cation-pi interactions, involving the DFG-loop residue F-169, which participate in the stabilization of an intermediate conformation and in its consequent transition to the DFG-out conformation. From this study, insights which may prove useful for inhibitor design and/or site directed mutagenesis studies are derived. (C) 2010 Elsevier Ltd. All rights reserved.