Benchmark calculations on models of the phosphoryl transfer reaction catalyzed by protein kinase A

Protein phosphorylation has been proved to be of great importance in many stages of cell life. In the last few years, its reaction mechanism has been extensively studied. In this work we present the analysis of the performances of several computational methods with different computational costs (from multilevel to semiempirical) to point out the best method to be used at each level in the study of phosphoryl transfer. Finally, we center on the semiempirical methods, and mainly on the AM1/d Hamiltonian with different sets of parameters, which will permit hybrid quantum mechanics/molecular mechanics (QM/MM) free energy calculations on big models at an acceptable computational cost. We have used quite a large set of molecules and model reactions to test the computational methods, reproducing all the chemical steps involved in the mainly accepted reaction pathways for the protein phosphorylation. In the end, we also present the results for an enlarged model, cut out from an entire biological model: we compare the 2-D PES at the B3LYP and AM1/d levels with the purpose of obtaining a correction for the semiempirical method. The AM1/d-PhoT semiempirical parameterization corrected using single-point energy calculations at the B3LYP/MG3S level seems to be suitable to carry out reliable QM/MM calculations of the complete biological system.