Quantum Chemical Calculation of the Enzyme-Ligand Interaction Energy for Trypsin Inhibition by Benzamidines

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Three-dimensional coordinates of the β-trypsin-benzamidine complex were used to construct a quantum chemical model for the enzyme-inhibitor interaction. The model included all enzyme and benzamidinium (H4N2CC6H4X+) atoms and two bound water molecules (W702 and W710) located near the binding site. Hydration was also treated by using a simple model of the first hydration sphere including four water molecules. The enzyme-inhibitor interaction energy was approximated as ∑Venz(ra)qawhere the first term is the enzyme electrostatic potential at the position of atom a and the second term is the charge on this atom. The potential was calculated from bond fragments as proposed previously while net charges were obtained from CNDO/2 calculations. The hydration energy was calculated by the same expression, where Venzwas replaced by the potential of the four water molecules. It was found that the experimental Gibbs free energy of association, ΔGexptl, depends linearly on the calculated interaction energy. A similar linear relationship was observed between the hydration energy and ΔGexptl, indicating that the enzyme may be treated as a “supersolvent”. The “electrostatic lock” representing the active site of the enzyme is characterized, and the “key” (the charge pattern of the inhibitor) is found to fit into this lock. With use of this model as a guide, simple structure-activity relationships are derived which may be extended to other enzymes, like thrombin and plasmin.

Original languageEnglish
Pages (from-to)4584-4589
Number of pages6
JournalJournal of the American Chemical Society
Issue number16
Publication statusPublished - Jan 1 1984

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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