Modeling the antiferromagnetic MnIIMnII system within the protein phosphatase-5 catalytic site

Protein phosphatase-5 (PP5), a novel target for inhibition in a search for new antitumor drugs, contains a homobimetallic Mn(II)Mn(II) system in its catalytic site. The ground electronic state is an antiferromagnetically-coupled singlet. We report optimizations of a known inhibitor within a 42-residue model of the PP5 catalytic site under several two-level hybrid ONIOM computational models. Using the high-resolution crystal structure of a PP5/inhibitor complex as reference, we compare geometric parameters as the qualities of the "high-level" and "low-level" wavefunctions are successively improved by using the correct antiferromagnetic (AF) singlet state. We find that the UB3LYP AF wavefunction for the high-level region is necessary for experimental fidelity. A closed-shell semi-empirical method (RPM6) can be used for the low-quality part of the hybrid scheme to afford geometries which are qualitatively on par with that obtained using the more time-consuming open-shell UB3LYP AF wavefunction. As the AF state can be elusive for such a large system, the ferromagnetic (F) state can also be used in the low-quality calculations without impacting the geometry.