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The Cooperative Effect Between Active Site Ionized Groups and Water Desolvation Controls the Alteration of Acid/Base Catalysis in Serine Proteases
Author(s) -
Shokhen Michael,
Khazanov Netaly,
Albeck Am
Publication year - 2007
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700241
Subject(s) - active site , chemistry , oxyanion hole , solvation , catalysis , catalytic triad , serine protease , transition state analog , carboxylate , enzyme catalysis , proteases , histidine , serine , chymotrypsin , tetrahedral carbonyl addition compound , stereochemistry , enzyme , organic chemistry , protease , solvent , trypsin , nucleophile
What is the driving force that alters the catalytic function of His57 in serine proteases between general base and general acid in each step along the enzymatic reaction? The stable tetrahedral complexes (TC) of chymotrypsin with trifluoromethyl ketone transition state analogue inhibitors are topologically similar to the catalytic transition state. Therefore, they can serve as a good model to study the enzyme catalytic reaction. We used DFT quantum mechanical calculations to analyze the effect of solvation and of polar factors in the active site of chymotrypsin on the p K a of the catalytic histidine in FE (the free enzyme), EI (the noncovalent enzyme inhibitor complex), and TC. We demonstrated that the acid/base alteration is controlled by the charged groups in the active site—the catalytic Asp102 carboxylate and the oxyanion. The effect of these groups on the catalytic His is modulated by water solvation of the active site.