Theoretical Study of Enzyme-Substrate Complex Formation by the Conformational Energy Analysis

利用高速计算机进行构象能分析是以很好的时空分辨率“看到”生物大分子动态构象的理论工具。本项目的目的是利用该方法对蛋白酶与其底物多肽形成复合体的过程进行模拟，并从多个角度对模拟结果进行分析。我们已经开发了一种快速计算构象能函数一阶和二阶导数的算法，以及使用前者的能量最小化和蒙特卡罗模拟方法。我们在上面的模拟中使用了这些方法。具体地说，我们模拟了一种蛋白水解酶SGPB与其抑制剂卵粘蛋白以及二氢叶酸还原酶与其抑制剂之间的络合物形成。从这些模拟的结果可以看出，蛋白质中存在两种类型的构象柔性，即谐和非谐，它们在复杂的形成过程中具有复杂的影响。因此，在一种小的球状蛋白BPTI中对这两个方面进行了更详细的研究。这两个方面的差异最直接地体现在蛋白质内部原子接触的拓扑结构上。在简谐方面，拓扑保持不变，而在非简谐方面，保持不变，即在这种构象变化的过程中，原子对的接触变化。非谐机制更容易引起局部构象变化。

The conformational energy analysis by the use of high-speed computer is a theoretical tool to "see" dynamic conformation of biopolymers by a very good space-time resolution. The purpose of this project is to carry out the simulation of the process of complex formation between proteinases and their substrate peptides by this method and to analyze the results from various points of view. We have already developed an algorithm to calculate first and second derivatives of the conformational energy function rapidly and the methods of energy minimization and Monte Carlo simulation, which use the former. We used these methods in the above simulation. To be specific, we carried out the simulation of complex formation between a proteinase SGPB and its inhibitor ovomucoid, and between dihydrofolate reductase and its inhibitor. From the results of these simulations, it is indicated that there are two types of conformational flexibilities, harmonic and anharmonic, in proteins and they have complicated influences in the processes of complex formation. Therefore these two aspects are studied in a more detail in a small globular protein, BPTI. The difference of the two aspects manifests most directly in the topology of atomic contacts in the protein interior. In the harmonic aspect, the topology is maintained, while in the anharmonic aspect it is not maintained, i.e., pairs of atoms incontact change in the process of such conformational changes. Local conformational changes can be induced more easily by the anharmonic mechanism.