DFT Evaluation of Metal Ion Selectivity in Protein Phosphatase PPM1A: The Effect of Native Metal Type and Multiplicity on the Competition with Other Biogenic Contenders for the Active Site

Protein phosphatase PPM1A plays a critical role in cellular signaling by dephosphorylating key regulatory proteins. According to experimental data, the enzyme requires either Mn2+ or Mg2+ bound in the active center(s), hence its catalytic activity strongly depends on the chelated metal ions. In this study, the metal ion selectivity of PPM1A is investigated using DFT calculations on active site constructs of bi- and trinuclear metal centers and protein ligands from the first and second metal coordination shells. Binuclear Mn-Mn and trinuclear Mn-Mn-Mn sites show poor resistance to substitution by biogenic Fe2+ and Zn2+, with Gibbs energies of the Mn2+ → Fe2+/Zn2+ exchange being consistently negative in both the gas phase and condensed media. In contrast, Mg-Mg and Mg-Mg-Mg centers are substantially more robust, with a thermodynamically unfavorable Mg2+ → Fe2+/Zn2+ substitution—except in the case of the Mg-Mg-Zn complex. The primary factors governing this metal competition in the modeled structures are the nature of the competing cation and the solvation properties of its aqua complexes, while solvent exposure of the binding site and the number of metal cations in the catalytic center exert a comparatively minor effect. Overall, these findings demonstrate that Mg2+-loaded active sites offer considerably greater protection against biogenic metal displacement than their Mn2+ counterparts, thus shedding light on the metalloprotein stability and enzyme fidelity of PPM1A.