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

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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.