Ab initio molecular orbital calculations on N-beta-mercaptoethylacetamide and its derivatives as model compounds of coenzyme A (CoA), acetyl-CoA, and malonyl-CoA

The conformational study on N-beta-mercaptoethylacetamide (MEA), acetyl-MEA, and malonyl-MEA as model compounds of coenzyme A (CoA), acetyl-CoA, and malonyl-CoA, respectively, is carried out using the ab initio method at the HF/6-31G* level and the hydration shell model in order to investigate the information on structures and energetics of the compounds when acetyl-CoA or malonyl-CoA is hydrolyzed into acetic acid and CoA or hydrogen malonate and CoA, respectively, in the gas phase and in solution. It is found that the overall preferred conformations of MEA are different from those of acetyl-MEA or malonyl-MEA and that the intramolecular hydrogen bond between amide hydrogen and terminal carboxylate oxygen is responsible for the low-energy conformations of malonyl-MEA. To determine the thermodynamic parameters in the gas phase at 298.15 K, the vibrational analysis was undertaken for minimized conformations. The preferred conformations and structural parameters of the three compounds are in accord with those of related compounds obtained from spectroscopic experiments and are reasonably consistent with the corresponding data of CoA and its derivatives complexed with CoA-binding proteins deduced from X-ray and NMR studies to within experimental uncertainty. For the hydrolysis of acetyl-MEA and malonyl-MEA in aqueous solution, total free energy changes (Delta G(tot)) are computed to be -12.4 and -22.5 kcal/mol, respectively, of which the former is in good agreement with the experimental value of -13.8 +/- 0.1 kcal/mol for the hydrolysis of acetyl-CoA. Although computed free energy changes (ca. -15 kcal/mol) for the two reactions in the gas phase are almost the same, the hydration appears to raise and lower the Delta G(tot) for the hydrolysis of acetyl-MEA and malonyl-MEA, respectively. The more negative value of Delta G(tot) for the hydrolysis of malonyl-MEA in solution implies that the malonyl-CoA may have a higher group transfer potential than the acetyl-CoA.