Is There a Weak H-bond → LBHB Transition on Tetrahedral Complex Formation in Serine Proteases?

Michael Shokhen, Amnon Albeck

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25 Scopus citations


The transformation of a weak hydrogen bond in the free enzyme into a low-barrier hydrogen bond (LBHB) in the tetrahedral intermediate has been suggested as an important factor facilitating catalysis in serine proteases. In this work, we examine the structure of the H-bond in the Asp102-His57 diad of serine proteases in the free enzyme and in a covalent tetrahedral complex (TC) with a trifluoromethylketone inhibitor. We apply ab initio quantum mechanical calculations to models consisting of a large molecular fragment of the enzyme active site, and the combined effect of the rest of the protein body and the solvation by surrounding bulk water was simulated by a self-consistent reaction field method in our novel QM/SCRF(VS) approach. Potential profiles of adiabatic proton transfer in the Asp102-His57 diad in these model systems were calculated. We conclude that the hydrogen bond in both the free enzyme and in the enzyme-inhibitor TC is a strong ionic asymmetric one-well hydrogen bond, in contrast to a previous suggestion that it is a weak H-bond in the former and a double-well LBHB in the latter.

Original languageEnglish
Pages (from-to)468-477
Number of pages10
JournalProteins: Structure, Function and Genetics
Issue number3
StatePublished - 15 Feb 2004


  • Enzyme mechanism
  • Hydrogen bonds
  • Quantum mechanical calculations


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