The metal dication Pb(II) is known to promote catalytic cleavage of the sugar phosphate backbone in tRNA. The mechanism proposed to achieve this step requires that the [Pb(II)OH-](+) moiety act as a nucleophile and alter the local acidity of surrounding water molecules. MP2 calculations investigating the effect that nonaqueous bases have on the stability of dihydrated-Pb(II) show that the height and position of the proton-transfer barrier are sensitive to the presence of a single N- or O-coordinating "spectator" ligand and that, with the addition of two ligands coordinated directly to the Pb(II) center, the equilibrium for the hydrolysis reaction can shift to the left, thus making the Pb(II)-hydrate complex more stable than the Pb(II)-hydroxide complex. The calculations reveal a good correlation between the gas-phase basicities of nonaqueous ligands coordinated to the metal center and the barriers to proton transfer in [Pb(H2O)(2)](2+). In terms of the Pb(II)-induced hydrolysis of tRNA, these results indicate that the coordination of [Pb(II)-OH-](+) to uracil and cytosine in tRNA increases the basicity of the hydroxyl group and promotes nucleophilic attack of H+.