Ion pair formation of phosphorylated amino acids and lysine and arginine side chains: a theoretical study

Protein phosphorylation is one of the major signal transduction mechanisms for controlling and regulating intracellular processes. Phosphorylation of specific hydroxylated amino acid side chains (Ser, Thr, Tyr) by protein kinases can activate numerous enzymes; this effect can be reversed by the action of protein phosphatases. Here we report ab initio (HF/6-31G and Becke3LYP/6-31G) and semiempirical (PM3) molecular orbital calculations pertinent to the ion pair formation of the phosphorylated amino acids with the basic side chains of Lys and Arg. Methyl-, ethyl-, and phenylphosphate, as well as methylamine and methylguanidinium were used as model compounds for the phosphorylated and basic amino acids, respectively. Phosphorylated amino acids were calculated as mono- and divalent anions. Our results indicate that the PSer/PThr ion pair interaction energies are stronger than those with PTyr. Moreover, the interaction energies with the amino group of Lys are generally more favorable than with the guanidinium group of Arg. The Lys amino groups form stable bifurcated hydrogen bonded structures; while the Arg guanidinium group can form a bidentate hydrogen bonded structure. Reasonable values for the interaction free energies in aqueous solution were obtained for some complexes by the inclusion of a solvent reaction field in the computation (PM3-SM3).