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Electrostatic contributions to binding of transition state analogues can be very different from the corresponding contributions to catalysis: phenolates binding to the oxyanion hole of ketosteroid isomerase
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 6, 1466-1476 p.Article in journal (Refereed) Published
Abstract [en]

The relationship between binding of transition state analogues (TSAs) and catalysis is an open problem. A recent study of the binding of phenolate TSAs to ketosteroid isomerase (KSI) found a small change in the binding energy with a change in charge delocalization of the TSAs. This has been taken as proof that electrostatic effects do not contribute in a major way to catalysis. Here we reanalyze the relationship between the binding of the TSAs and the chemical catalysis by KSI as well as the binding of the transition state (TS), by computer simulation approaches. Since the simulations reproduce the relevant experimental results, they can be used to quantify the different contributions to the observed effects. It is found that the binding of the TSA and the chemical catalysis represent different thermodynamic cycles with very different electrostatic contributions. While the binding of the TSA involves a small electrostatic contribution, the chemical catalysis involves a charge transfer process and a major electrostatic contribution due to the preorganization of the active site. Furthermore, it is found that the electrostatic preorganization contributions to the binding of the enolate intermediate of KSI and the TS are much larger than the corresponding effect for the binding of the TSAs. This reflects the dependence of the preorganization on the orientation of the nonpolar form of the TSAs relative to the oxyanion hole. It seems to us that this work provides an excellent example of the need for computational studies in analyzing key experimental findings about enzyme catalysis.

Place, publisher, year, edition, pages
2007. Vol. 46, no 6, 1466-1476 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-14713DOI: 10.1021/bi061752uISI: 000243989500002PubMedID: 17279612OAI: oai:DiVA.org:uu-14713DiVA: diva2:42484
Available from: 2008-01-31 Created: 2008-01-31 Last updated: 2011-02-15Bibliographically approved

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