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Electrocatalytic water oxidation using the oxidatively robust 2,7-[bis(2-pyridylmethyl)aminomethyl]-1,8-naphthyridine ligand (BPMAN)-based dinuclear copper(II) complex, [Cu2(BPMAN)(μ-OH)](3+), has been investigated. This catalyst exhibits high reactivity and stability towards water oxidation in neutral aqueous solutions. DFT calculations suggest that the O-O bond formation takes place by an intramolecular direct coupling mechanism rather than by a nucleophilic attack of water on the high-oxidation-state Cu(IV)=O moiety.

We report systematic quantum mechanics-only (QM-only) and QM/molecular mechanics (MM) calculations on an enzyme-catalyzed reaction to assess the convergence behavior of QM-only and QM/MM energies with respect to the size of the chosen QM region. The QM and MM parts are described by density functional theory (typically B3LYP/def2-SVP) and the CHARMM force field, respectively. Extending our previous work on acetylene hydratase with QM regions up to 157 atoms (Liao and Thiel, J. Chem. Theory Comput. 2012, 8, 3793), we performed QM/MM geometry optimizations with a QM region M4 composed of 408 atoms, as well as further QM/MM single-point calculations with even larger QM regions up to 657 atoms. A charge deletion analysis was conducted for the previously used QM/MM model (M3a, with a QM region of 157 atoms) to identify all MM residues with strong electrostatic contributions to the reaction energetics (typically more than 2 kcal/mol), which were then included in M4. QM/MM calculations with this large QM region M4 lead to the same overall mechanism as the previous QM/MM calculations with M3a, but there are some variations in the relative energies of the stationary points, with a mean absolute deviation (MAD) of 2.7 kcal/mol. The energies of the two relevant transition states are close to each other at all levels applied (typically within 2 kcal/mol), with the first (second) one being rate-limiting in the QM/MM calculations with M3a (M4). QM-only gas-phase calculations give a very similar energy profile for QM region M4 (MAD of 1.7 kcal/mol), contrary to the situation for M3a where we had previously found significant discrepancies between the QM-only and QM/MM results (MAD of 7.9 kcal/mol). Extension of the QM region beyond M4 up to M7 (657 atoms) leads to only rather small variations in the relative energies from single-point QM-only and QM/MM calculations (MAD typically about 1-2 kcal/mol). In the case of acetylene hydratase, a model with 408 QM atoms thus seems sufficient to achieve convergence in the computed relative energies to within 1-2 kcal/mol.

Acetylene hydratase is a tungsten-dependent enzyme that catalyzes the nonredox hydration of acetylene to acetaldehyde. Density functional theory calculations are used to elucidate the reaction mechanism of this enzyme with a large model of the active site devised on the basis of the native X-ray crystal structure. Based on the calculations, we propose a new mechanism in which the acetylene substrate first displaces the W-coordinated water molecule, and then undergoes a nucleophilic attack by the water molecule assisted by an ionized Asp13 residue at the active site. This is followed by proton transfer from Asp13 to the newly formed vinyl anion intermediate. In the subsequent isomerization, Asp13 shuttles a proton from the hydroxyl group of the vinyl alcohol to the α-carbon. Asp13 is thus a key player in the mechanism, but also W is directly involved in the reaction by binding and activating acetylene and providing electrostatic stabilization to the transition states and intermediates. Several other mechanisms are also considered but the energetic barriers are found to be very high, ruling out these possibilities.enzyme catalysis | metalloenzyme | cluster approach T ungsten is the heaviest metal in biology and plays prominent roles in carbon, nitrogen, and sulfur metabolisms (1-6). In all known tungstoenzymes, the tungsten ion coordinates to the dithiolene group of two pterin cofactors and has oxidation numbers ranging from þ4 to þ6. Three families of enzymes have been discovered to be tungsten-dependent, namely aldehyde oxidoreductase, formate dehydrogenase, and acetylene hydratase (AH) (1). The former two are involved in oxidative reactions, whereas the third one catalyzes the nonredox hydration of acetylene (Scheme 1) in the anaerobic unsaturated hydrocarbon metabolism (7). This reaction is exothermic by about 27 kcal∕mol, and the resulting acetaldehyde can be further oxidized to provide a significant source of carbon and energy for certain bacteria (8).The crystal structure of AH from Pelobacter acetylenicus has been solved by Seiffert et al. at 1.26-Å resolution, and it reveals a mononuclear tungsten center in the active site and a nearby iron-sulfur cubane cluster (9). In the active site, the tungsten ion is ligated by the four sulfur atoms of the two pterin dithiolene moieties, Cys141, and an oxygen species, which was assigned to be a water molecule. A second-shell residue, Asp13, is found to hydrogen-bond to the oxygen species and was suggested to be in the protonated form, based on pH titration calculations using continuum electrostatics and statistical thermodynamics (9). However, the ionized form of Asp13 cannot be ruled out because the crystal structure shows that it has two additional hydrogen bonds, to the peptide bond of Cys12-Asp13 and the side chain of Trp179, which would lower the pK a significantly. An arginine residue (Arg606) is also located close to the two pterins, providing electrostatic stabilization to the cofactors. Based on studies of biomimetic complexes of AH (10) and redox titration...