pKa optimized catalysis in serine proteinases, an ab initio study on the catalaytic His

Authors

  • Péter Hudáky,

    1. Laboratory of Structural Chemistry and Biochemistry, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117, Budapest, Hungary
    2. Protein Modelling Group HAS-ELTE, Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest P.O.B 32, Hungary
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  • András Perczel

    Corresponding author
    1. Laboratory of Structural Chemistry and Biochemistry, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter sétány 1/A, H-1117, Budapest, Hungary
    2. Protein Modelling Group HAS-ELTE, Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest P.O.B 32, Hungary
    • Protein Modelling Group HAS-ELTE, Institute of Chemistry, Eötvös Loránd University, H-1117 Budapest P.O.B 32, Hungary
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Abstract

First principle models of catalytic apparatus of enzymes can be used for studying stability as well as the atomic details of a catalytic mechanism. For example, the catalytic triad of chymotrypsin was recently investigated by using an ab initio geometry optimized (Hudáky and Perczel, Proteins: Struct Funct Genet, 2006, 62, 749) self-stabilizing molecule ensemble without the presence of the complete enzyme and substrate. Several parameters of the above catalytic reaction turned out to be the same within the model and the in vitro enzymatic reaction. Among the numerous parameters of the catalytic process geometrical changes of the catalytic histidine was investigated here and the variation of its pKa value was determined. A relatively large range, 3.5 unit, was determined as the variation of pKa as function of the conformational subspace available in serine proteases. Comparing PDB structures of the free and the complex enzymes it was shown, that histidine, after accepting the proton from the OH group of the catalytic serine, undergoes a minor conformational change accompanied by a 2.5 unit decrease in pKa. We conclude that the changes of pKa during catalysis are predominantly determined by the geometrical arrangement of the histidine moiety and this change serves as a significant driving force in the catalytic process. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007

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