Probing the Allosteric Mechanism in Pyrrolysyl-tRNA Synthetase Using Energy-Weighted Network Formalism
Probing the Allosteric Mechanism in Pyrrolysyl-tRNA Synthetase Using Energy-Weighted Network Formalism
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DOI：
10.1021/bi200306u
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发表时间：
2011-07-19
期刊：
影响因子：
2.9
通讯作者：
Vishyeshwara, Saraswathi
中科院分区：
文献类型：
--
作者：
Bhattacharyya, Moitrayee;Vishyeshwara, Saraswathi
吡咯酰-tRNA合成酶是一种非典型的酶，它负责将吡咯赖氨酸带入tRNA(Pyl)，尽管缺乏对tRNA反密码子的精确识别。这种二聚体蛋白表现出变构调节功能，就像任何其他tRNA合成酶一样。在这项研究中，我们通过脱硫杆菌Hafniense PyIRS(DhPyIRS)及其与tRNA(Pyl)和活化的吡咯赖氨酸的络合物的能量加权网络，在原子水平上研究了变构通讯的途径。我们对这些配合物的结构进行了分子动力学模拟，以获得系综构象布居的观点。在DhPylRS的结构网络中识别导致最短通信路径的关键残基和交互作用时，探索了与识别社交网络环境中的关键参与者和纽带相关的加权图参数，例如边/节点介入度、贴近度指数和漏斗的概念。此外，还评估了由于配体诱导的扰动而导致的重要残基和连接状态的变化以及通信成本。研究了最优路径、次优路径和预先存在的路径。这些参数中的许多都显示了二聚体蛋白质两个亚基之间的增强的不对称性，特别是在转移前复合体中，这使得我们得出结论，功能的编码超出了蛋白质的序列/结构。由适当配体介导的局部和全局扰动及其对构象平衡系综的影响在蛋白质的功能中也起着重要的作用。综上所述，我们认为许多功能方面(DhPyIRS中的变构和半位反应性)的起源在于在全球水平上相互作用和动力学的微妙重排。
Pyrrolysyl-tRNA synthetase (PyIRS) is an atypical enzyme responsible for charging tRNA(Pyl) with pyrrolysine, despite lacking precise tRNA anticodon recognition. This dimeric protein exhibits allosteric regulation of function, like any other tRNA synthetases. In this study we examine the paths of allosteric communication at the atomic level, through energy-weighted networks of Desulfitobacterium hafniense PyIRS (DhPyIRS) and its complexes with tRNA(Pyl) and activated pyrrolysine. We performed molecular dynamics simulations of the structures of these complexes to obtain an ensemble conformation-population perspective. Weighted graph parameters relevant to identifying key players and ties in the context of social networks such as edge/node betweenness, closeness index, and the concept of funneling are explored in identifying key residues and interactions leading to shortest paths of communication in the structure networks of DhPylRS. Further, the changes in the status of important residues and connections and the costs of communication due to ligand induced perturbations are evaluated. The optimal, suboptimal, and preexisting paths are also investigated. Many of these parameters have exhibited an enhanced asymmetry between the two subunits of the dimeric protein, especially in the pretransfer complex, leading us to conclude that encoding of function goes beyond the sequence/structure of proteins. The local and global perturbations mediated by appropriate ligands and their influence on the equilibrium ensemble of conformations also have a significant role to play in the functioning of proteins. Taking a comprehensive view of these observations, we propose that the origin of many functional aspects (allostery rand half-sites reactivity in the case of DhPyIRS) lies in subtle rearrangements of interactions and dynamics at a global level.