ISSN:
0020-7608
Keywords:
Computational Chemistry and Molecular Modeling
;
Atomic, Molecular and Optical Physics
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
Quantum mechanical calculations have been used to study the reaction mechanism of human carbonic anhydrase-catalyzed hydration of CO2. This reaction is responsible for fast metabolism of CO2 in the human body. For each of the reaction steps, possible catalytic effects of active site residues are examined. The pertinent results are as follows. (1) For CO2 binding, the experimentally observed 2.5 cm-1 frequency shift of the asymmetic stretching frequency between measurements taken in the aqueous solution and in the enzyme is reproduced in our theoretical calculations. Our results suggest that CO2 binds to the zinc ion within the hydrophobic pocket. (2) No energy barrier is found for the nucleophilic attack from Zn2+-bound OH- to C of CO2 to form Zn2+-bound HCO3-. (3) For the internal proton transfer within zinc-bound HCO3-, the barrier of 35.6 kcal/mol for the direct internal proton transfer is reduced to 3.5 and 1.4 kcal/mol, respectively, when one or two water molecules are included for proton relay. (4) Displacement of Zn2+-bound HCO3- by H2O is facilitated by the presence of the negatively charged Glu 106-Thr 199 chain and by the association and the subsequent ionization of a fifth water ligand. (5) For the intramolecular proton transfer between Zn2+-bound H2O and His 64, the Zn2+ ion lowers the pKa of Zn2+-bound water and repels the proton. His 64, or a similar proton receptor with a larger proton affinity than H2O, functions as proton receiver; and the active site water molecules visualized by x-ray crystallography are important for the proton relay function. In summary, it is demonstrated that in order to achieve effective catalysis, a sequence of precisely coordinated catalytic events among all participating catalytic elements in the enzyme's active site is essential.
Additional Material:
6 Ill.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/qua.560360313
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