A recent crystal structure of the precleaved HDV ribozyme along with biochemical data support a mechanism for phosphodiester bond self-cleavage in which C75 acts as a general acid and bound Mg2+ ion acts as a Lewis acid. Herein this precleaved crystal structure is used as the basis for quantum mechanical/molecular mechanical calculations. These calculations indicate that the self-cleavage reaction is concerted with a phosphorane-like transition state when a divalent ion, Mg2+ or Ca2+, is bound at the catalytic site but is sequential with a phosphorane intermediate when a monovalent ion, such as Na+, is at this site. Electrostatic potential calculations suggest that the divalent metal ion at the catalytic site lowers the pKa of C75, leading to the concerted mechanism in which the proton is partially transferred to the leaving group in the phosphorane-like transition state. These observations are consistent with experimental data, including pKa measurements, reaction kinetics, and proton inventories with divalent and monovalent ions.
All Science Journal Classification (ASJC) codes
- Materials Science(all)
- Physical and Theoretical Chemistry