AMI and PM3 study of a low molecular weight structural mimic of hydrogen exchange within the catalytic center of aspartic proteases
✍ Scribed by Jerzy Ciarkowski; Stanislaw Oŀdziej
- Publisher
- Springer
- Year
- 1993
- Tongue
- English
- Weight
- 630 KB
- Volume
- 22
- Category
- Article
- ISSN
- 1432-1017
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✦ Synopsis
Based on recent X-ray studies, a low molecular weight model of the active center of aspartic proteases is proposed. The model is small enough to enable unattended geometry optimizations (including search for saddlepoints) by molecular orbital methods. It consists of two malonic acid molecules and a water molecule; there is a carboxylic dimer at one end and the water molecule is located between the carboxylate and the carboxyl group at the other. The latter structure reproduces the geometry of the catalytic center of the native enzyme penicillopepsin with a root-mean-square deviation of 0.46 ~ for five O--O distances. The AM1 and PM3 molecular orbital methods were used to study the H-bond exchange within the model. Both methods lead consistently to the following conclusions: Among 2 pairs of symmetryequivalent stationary states of the catalytic center there are at least 4 symmetry-independent hydrogen-exchange pathways, and many more when including symmetry of the center. Energetics and geometry of all identified pathways are presented. In summary, they result in "juggling" all three active center protons (COOH and HOH) among all five active center oxygens (COO-, COOH and H20 ) providing the center with a high delocalisation with respect to the actual position of its anionic site and/or its protonation status. The relevance of the delocalisation of the acidic proton to the mechanism of enzymatic action is briefly discussed.