Comp Chem Research Developments

Hybrid QM/MM study of thio effects in transphosphorylation reactions in solution

Reactions that involve the hydrolysis (or transesterification) of phosphodiester bonds are of fundamental importance in biology, especially in the study of the molecular mechanisms of RNA catalysis. A powerful experimental technique to probe the mechanism of phosphate transesterification and hydrolysis is to introduce chemical modifications to the reactive phosphate in key positions, and measure the effect on the reaction rate. One particularly useful modification involves the substitution of phosphoryl oxygens by sulfur. A subsequent reduction in the reaction rate is known as a "thio effect". The mechanistic interpretations of thio effects, especially in enzymatic reactions, are often a topic of considerable debate, since it may not be clear, at a molecular level, what gives rise to the change in activation free energy. Theory provides an extremely powerful tool to aid in the interpretation and detailed understanding of experimentally determined thio effects.

The first step toward the understanding of thio effects in catalytic RNA systems is to properly model the corresponding reactions in solution. Recently, graduate student Brent Gregersen and Professor Darrin York of the Department of Chemistry, in collaboration with Chemistry Professor (University of the Basque Country) and Minnesota Supercomputing Institute research scholar Xabier Lopez, have reported results of a series of activated dynamics calculations of thio effects on the transesterification reaction of an RNA sugar-phosphate model in solution (Fig. 1a). The simulations employed a new combined quantum mechanical/molecular mechanical approach to determine the reaction free energy profiles (Fig. 1b). The results are in excellent agreement with known experimental studies and provide the first detailed look at the balance between electronic and solvation effects that give rise to the drastically different observed reactions profiles. These results have been published as a communication in the Journal of the American Chemical Society 125, 7178-7179 (2003). The work represents a key step in the ongoing research of the York group focused on the design and application of theoretical methods to study RNA catalysis.

Fig. 1a

Fig. 1b

Figure Caption:  (a) In-line dianionic mechanism of transphosphorylation, (b) Reaction profiles showing thio effects for the in-line dianionic mechanism. Free energies relative to the reactants are shown as a function of the reaction coordinate (r₁- r₂) where r₁ and r₂ are the P...X2' and P...X5' distances, respectively.