Ghosh Amit, Vishveshwara Saraswathi
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India 560012.
Biochemistry. 2008 Nov 4;47(44):11398-407. doi: 10.1021/bi8007559. Epub 2008 Oct 9.
The allosteric concept has played a key role in understanding the biological functions of proteins. The rigidity or plasticity and the conformational population are the two important ideas invoked in explaining the allosteric effect. Although molecular insights have been gained from a large number of structures, a precise assessment of the ligand-induced conformational changes in proteins at different levels, ranging from gross topology to intricate details, remains a challenge. In this study, we have explored the conformational changes in the complexes of methionyl tRNA synthetase (MetRS) through novel network parameters such as cliques and communities, which identify the rigid regions in the protein structure networks (PSNs) constructed from the noncovalent interactions of amino acid side chains. MetRS belongs to the aminoacyl tRNA synthetase (aaRS) family that plays a crucial role in the translation of genetic code. These enzymes are modular with distinct domains from which extensive genetic, kinetic, and structural data are available, highlighting the role of interdomain communication. The network parameters evaluated here on the conformational ensembles of MetRS complexes, generated from molecular dynamics simulations, have enabled us to understand the interdomain communication in detail. Additionally, the characterization of conformational changes in terms of cliques and communities has also become possible, which had eluded conventional analyses. Furthermore, we find that most of the residues participating in cliques and communities are strikingly different from those that take part in long-range communication. The cliques and communities evaluated here for the first time on PSNs have beautifully captured the local geometries in detail within the framework of global topology. Here the allosteric effect is revealed at the residue level via identification of the important residues specific for structural rigidity and functional flexibility in MetRS. This ought to enhance our understanding of the functioning of aaRS in general.
变构概念在理解蛋白质的生物学功能方面发挥了关键作用。刚性或可塑性以及构象群体是解释变构效应时所涉及的两个重要概念。尽管已经从大量结构中获得了分子层面的见解，但要精确评估配体诱导的蛋白质在不同层面（从总体拓扑结构到复杂细节）的构象变化，仍然是一项挑战。在本研究中，我们通过新颖的网络参数（如团和群落）探索了甲硫氨酰 - tRNA合成酶（MetRS）复合物中的构象变化，这些参数可识别由氨基酸侧链的非共价相互作用构建的蛋白质结构网络（PSN）中的刚性区域。MetRS属于氨酰 - tRNA合成酶（aaRS）家族，在遗传密码的翻译中起关键作用。这些酶具有模块化的不同结构域，有大量的遗传、动力学和结构数据可用，突出了结构域间通信的作用。在此对由分子动力学模拟生成的MetRS复合物的构象集合评估的网络参数，使我们能够详细了解结构域间的通信。此外，根据团和群落对构象变化进行表征也成为可能，而这是传统分析所无法做到的。此外，我们发现参与团和群落的大多数残基与参与长程通信的残基明显不同。本文首次在PSN上评估的团和群落，在全局拓扑结构框架内详细地完美捕捉了局部几何结构。在这里，通过识别MetRS中对结构刚性和功能灵活性具有特异性的重要残基，在残基水平揭示了变构效应。这应该会增强我们对一般aaRS功能的理解。
