Thio Effects as a Tool for Mechanistic Studies of the Cleavage of RNA Phosphodiester Bonds: The Chemical Basis

Abstract

Replacement of one of the phosphorus-bound oxygen atoms with sulfur has extensively been used for elucidation of mechanistic details of the cleavage of RNA phosphodiester bonds by ribozymes. Since sulfur atom is larger, less electronegative, and more readily polarizable than oxygen, this substitution affects in many ways metal ion binding and the ease of formation and breakdown of the phosphorane intermediate/transition state obtained by the attack of the entering hydroxyl group on the phosphorus atom. The factors that may be altered by thio substitution include the geometry of the phosphorane intermediate, relative apicophilicities of the ligands, the leaving group property, hydrogen bonding, solvation, and the affinity to metal ions. Experimental studies and theoretical calculations on various model systems have been undertaken to obtain a solid chemical basis for the mechanistic interpretations based on thio effects in ribozyme catalysis. The results of such studies are surveyed in this chapter.