QM/MM Studies of Hairpin Ribozyme Self-Cleavage Suggest the Feasibility of Multiple Competing Reaction Mechanisms

Investor logo
Investor logo

Warning

This publication doesn't include Faculty of Economics and Administration. It includes Central European Institute of Technology. Official publication website can be found on muni.cz.
Authors

MLÝNSKÝ Vojtěch BANÁŠ Pavel WALTER Nils G. ŠPONER Jiří OTYEPKA Michal

Year of publication 2011
Type Article in Periodical
Magazine / Source JOURNAL OF PHYSICAL CHEMISTRY B
MU Faculty or unit

Central European Institute of Technology

Citation
Web http://pubs.acs.org/doi/abs/10.1021/jp206963g
Doi http://dx.doi.org/10.1021/jp206963g
Field Physical chemistry and theoretical chemistry
Keywords TRANSITION-STATE STABILIZATION; BASE-PHOSPHATE INTERACTIONS; DENSITY-FUNCTIONAL THEORY; MATRIX PROPAGATION ADMP; DELTA-VIRUS RIBOZYME; ACTIVE-SITE ADENINE; MOLECULAR-DYNAMICS; STRUCTURAL DYNAMICS; ENZYMATIC-REACTIONS; PHOSPHORYL TRANSFER
Description The hairpin ribozyme is a prominent member of small ribozymes since it does not require metal ions to achieve catalysis. Guanine 8 (G8) and adenine 38 (A38) have been identified as key participants in self-cleavage and -ligation. We have carried out hybrid quantum-mechanical/molecular mechanical (QM/MM) calculations to evaluate the energy along several putative reaction pathways. The error of our DFT description of the QM region was tested and shown to be similar to 1 kcal/mol. We find that self-cleavage of the hairpin ribozyme may follow several competing microscopic reaction mechanisms, all with calculated activation barriers in good agreement with those from experiment (20-21 kcal/mol). The initial nucleophilic attack of the A-1(2'-OH) group on the scissile phosphate is predicted to be rate-limiting in all these mechanisms. An unprotonated G8(-) (together with A38H(+)) yields a feasible activation barrier (20.4 kcal/mol). Proton transfer to a nonbridging phosphate oxygen also leads to feasible reaction pathways. Finally, our calculations consider thio-substitutions of one or both nonbridging oxygens of the scissile phosphate and predict that they have only a negligible effect on the reaction barrier, as observed experimentally.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.