title: Modeling the antiferromagnetic MnIIMnII system within the protein phosphatase-5 catalytic site.
abstract: 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.
authors.affiliation: Department of Chemistry, University of South Alabama, Mobile, AL, 36688, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Salter
authors.forename: R E
authors.initials: RE
authors.lastname: Honkanen
authors.forename: A
authors.initials: A
authors.lastname: Wierzbicki
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008345:Manganese / Q000737:chemistry*; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D008345:Manganese; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5