The generalized energy-based fragmentation (GEBF) approach (Li, W.; Li, S.; Jiang, Y. J. Phys. Chem. A 2007, 111, 2193) is extended for geometry optimizations and vibrational spectra calculations of general large molecules or clusters. In this approach, the total energy and its derivatives, and some molecular properties, of a target system are obtained from conventional calculations on a series of subsystems derived from the target system. Each subsystem is electronically embedded in the background point charges generated by all other atoms outside the subsystem so that the long-range interactions and polarization effects between remote fragments are approximately taken into account. The approach computationally scales linearly with the system size and can be easily implemented for large-scale parallelization. By comparing the results from the conventional and GEBF calculations for several test molecules including a polypeptide and a water cluster, we demonstrate that the GEBF approach is able to provide quite reliable predictions for molecular geometries, vibrational frequencies, and thermochemistry data and satisfactory descriptions for vibrational intensities, for general molecules with polar or charged groups.

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...

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