氨酰tRNA合成酶(aaRS),一类普遍存在的必需酶,可以结合靶tRNA并催化遗传密码翻译中的氨基酰化反应。在这项工作中,我们使用分子动力学模拟结合基于扭转互信息的网络模型,探索游离和结合状态下人类线粒体苯丙氨酰-tRNA合成酶(hmPheRS)的动态特性和变构通讯,以了解其tRNAPhe识别和变构的机制。我们的结果表明,hmPheRS的残基迁移率和残基间运动耦合被tRNAPhe结合显着增强,并且发生强烈的变构通讯,这对氨基酰化反应至关重要,提示tRNAPhe结合在酶功能中的重要作用。确定的信号通路主要使反密码子结合域(ABD)和催化域(CAD)之间的连接,以及在由许多功能片段和活性位点组成的CAD中,揭示了它们协同作用并实现hmPheRS的氨基酰化功能的共调节作用。此外,沿着通讯途径的几个关键残基被鉴定为参与介导ABD的反密码子识别和CAD的激活过程之间的协同偶联,显示了它们在变构网络中的关键作用,这与实验观察结果非常吻合。本研究揭示了hmPheRS中的变构通讯机制,可以为基于结构的靶向aaRS的药物设计提供重要信息。
Aminoacyl-tRNA synthetases (aaRSs), a family of ubiquitous and essential enzymes, can bind target tRNAs and catalyze the aminoacylation reaction in genetic code translation. In this work, we explore the dynamic properties and allosteric communication of human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS) in free and bound states to understand the mechanisms of its tRNAPhe recognition and allostery using molecular dynamics simulations combined with the torsional mutual information-based network model. Our results reveal that hmPheRS\'s residue mobility and inter-residue motional coupling are significantly enhanced by tRNAPhe binding, and there occurs a strong allosteric communication which is critical for the aminoacylation reaction, suggesting the vital role of tRNAPhe binding in the enzyme\'s function. The identified signaling pathways mainly make the connections between the
anticodon binding domain (ABD) and catalytic domain (CAD), as well as within the CAD composed of many functional fragments and active sites, revealing the co-regulation role of them to act coordinately and achieve hmPheRS\'s aminoacylation function. Besides, several key residues along the communication pathways are identified to be involved in mediating the coordinated coupling between
anticodon recognition at the ABD and activation process at the CAD, showing their pivotal role in the allosteric network, which are well consistent with the experimental observation. This
study sheds light on the allosteric communication mechanism in hmPheRS and can provide important information for the structure-based drug design targeting aaRSs.