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Communication

Hybrid QM/MM Study of Thio Effects in Transphosphorylation Reactions

Supporting Info

Brent A. Gregersen,^† Xabier Lopez,^‡ and Darrin M. York*^†

Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, and Kimika Fakultatea, P.K. 1072, 20080 Donostia, Euskadi, Spain

J. Am. Chem. Soc., 2003, 125 (24), pp 7178–7179

DOI: 10.1021/ja035167h

Publication Date (Web): May 23, 2003

†

University of Minnesota.

‡

Kimika Fakultatea.

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

york@chem.umn.edu

Abstract

Results of a series of hybrid quantum mechanical/molecular mechanical (QM/MM) activated dynamics simulations of thio effects in the transphosphorylation (methanolysis) of a 2‘-ribose, 5‘-methyl phosphate-diester under basic conditions are presented. Single and double substitutions in the nonbridging oxygen positions exhibit thio effects in accord with experimental data and show the existence of a stable intermediate. Thio substitution at the 2‘ and 5‘ positions resulted in reactions having a single transition state with increased and decreased free energy barriers, respectively, relative to the unsubstituted reaction. In all of the reactions except for the 5‘ substitution, the rate-limiting step corresponds to exocyclic cleavage. In the 5‘ substitution reaction, the rate-limiting step corresponds to endocyclic cleavage and shows a considerable reverse thio effect, in accord with experimental observations of phosphates with enhanced leaving groups. Thio substitution at the 3‘ position results in a mild reverse thio effect that arises from electronic stabilization of the dianionic transition state. The results presented here provide an important step toward the development and application of new hybrid QM/MM methods that, combined with experiment, may provide a detailed picture of the molecular mechanisms of RNA catalysis.

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