title: Is there a weak H-bond --> LBHB transition on tetrahedral complex formation in serine proteases?
abstract: 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.
authors.affiliation: The Julius Spokojny Bioorganic Chemistry Laboratory, Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel. shokhen@mail.biu.ac.il
authors.forename: Michael
authors.initials: M
authors.lastname: Shokhen
authors.forename: Amnon
authors.initials: A
authors.lastname: Albeck
mesh_terms: D002918:Chymotrypsin / Q000737:chemistry; D003198:Computer Simulation; D006860:Hydrogen Bonding; D006868:Hydrolysis; D007659:Ketones / Q000737:chemistry; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D011522:Protons; D011789:Quantum Theory; D012697:Serine Endopeptidases / Q000737:chemistry*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry; D012997:Solvents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D007659:Ketones; D011522:Protons; D015842:Serine Proteinase Inhibitors; D012997:Solvents; D014867:Water; D012697:Serine Endopeptidases; D002918:Chymotrypsin