We present molecular mechanics and ab initio quantum mechanical calculations on some cyclic nucleotides and analogues with the goal of accounting for the unusually exothermic heats of hydrolysis of the six membered ring containing phosphodiester, 3’,5'-cyclic adenosine monophosphate (AMP), and of the five membered ring containing phosphodiester, 2’,3'-cyclic AMP. We attribute the greater exothermicity for hydrolysis of 3’,5'-cyclic AMP and the corresponding simple model-compounds relative to that for trimethylene phosphate (8 kcal/mol) to the following effects: (1) the trans ring fusion in 3’,5'-cyclic AMP, which leads to 4-5 kcal/mol of strain energy in this molecule, and (2) the presence in the 3’,5'-cyclic nucleotide of an unfavorable O-C-C-O interaction which is relieved upon phosphate ring cleavage. This second interaction, which is solvent dependent, can account for about 1 -2 kcal/mol of the difference in hydrolysis energy. (3) This leaves approximately 1-2 kcal/mol unaccounted for, and this may arise from differential solvation energies of the reactant and product. Our calculations overestimate the exothermicity of hydrolysis of the five membered ring containing phosphodiester, 2’,3'-cyclic AMP, but find, in agreement with experiment, that its exothermicity is much closer to the simple model phosphodiester, ethylene phosphate, than found in the corresponding six membered ring phosphodiesters.
ASJC Scopus subject areas
- Colloid and Surface Chemistry