First-principles determination of molecular conformations of cyclic adenosine 3',5'-monophosphate in gas phase and aqueous solution.

Extensive first-principles electronic structure calculations were performed in this study to explore the possible molecular structures and their concentration distribution of an intracellular second messenger, that is, cyclic adenosine 3',5'-monophosphate (cAMP), and its protonated form (cAMPH) in the gas phase and aqueous solution. The calculations resulted in prediction of four different stable conformers of cAMP and eight different stable conformers of cAMPH and their relative Gibbs free energies in the gas phase and aqueous solution. All of the computational results consistently demonstrate that the predominant conformers of cAMP and cAMPH are always the cAMP-chair-anti and cAMPH-chair2-syn conformers, respectively, in both the gas phase and aqueous solution. It has been demonstrated that the free energy barriers calculated for the intertransformation reactions between different conformers are very low (below approximately 6 kcal/mol) such that the intertransformation reactions between different conformers are very fast so that the concentration distribution of the system can quickly reach the thermodynamic equilibration during the process of binding with a protein. The calculated phenomenological pKa of 3.66 is in good agreement with the experimental pKa of 3.9 reported in literature, suggesting that the computational predictions resulted from this study are reasonable.