Strain energy in enzyme-substrate binding: An energetic insight into the flexibility versus rigidity of enzyme active site
Strain energy in enzyme-substrate binding: An energetic insight into the flexibility versus rigidity of enzyme active site
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DOI：
10.1016/j.comptc.2012.06.017
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发表时间：
2012-09-01
影响因子：
2.8
通讯作者：
Yang, Huijuan
中科院分区：
文献类型：
--
作者：
Guo, Xinchun;He, Deyong;Yang, Huijuan
阐明酶活性中心的结构特征对于理解酶催化反应机理和生物化学意义具有重要意义。以往的研究主要集中在酶与底物结合后的结构变化和原子运动上，而本文的重点是酶与底物结合的能量方面。在这项研究中，15个结构已知的，功能多样的酶-底物复合物检索从蛋白质数据库（PDB），然后在酶和底物的应变能，以及能量的贡献，非键相互作用和去溶剂化效应，由于结合使用混合计划的混合QM/MM，复杂的DFT理论，和经验PB/SA分析计算。结果表明，导出的能量项是很好的相互兼容，它们的组合表现出良好的协议与实验测得的亲和力。此外，应变能似乎赋予酶-底物复合物的特异性，而复合物的稳定性主要由非键合和去溶剂化方面决定。更重要的是，虽然从结构的角度来看，酶的活性位点只承担轻微的构象变化相比，底物分子的结合，前者的应变能是大大大于后者，这意味着一个混合的特点，显着的刚性和酶的活性位点也有一定的灵活性。(C)2012爱思唯尔有限公司版权所有。
Elucidating the structural properties of enzyme active site is fundamentally important for our understanding of the reaction mechanism and biochemical implication underlying enzyme catalysis. Instead of previous efforts that mainly concentrated on the structural change and atomic motion of enzyme system upon substrate binding, we herein dedicate our focuses to the energetic aspect of enzyme-substrate binding. In this study, 15 structure-known, functionally diverse enzyme-substrate complexes are retrieved from the Protein Data Bank (PDB) and then the strain energies both in enzyme and in substrate as well as the energetic contributions from nonbonded interaction and desolvation effect due to binding are calculated by using a mixed scheme of hybrid QM/MM, sophisticated DFT theory, and empirical PB/SA analysis. It is shown that the derived energy terms are well compatible to each other and their combination exhibits a good agreement with experimentally measured affinity. In addition, the strain energy appears to confer specificity for enzyme-substrate complex, whereas the stability, of the complex is primarily dominated by nonbonded and desolvation facets. More importantly, although from the structural point of view the enzyme active site only bears a slight conformational change as compared to substrate molecule in binding, the strain energy in former is substantially greater than that in latter, implying a mixed feature of significant rigidity and also some flexibility in enzyme active site. (C) 2012 Elsevier B.V. All rights reserved.