QM optimizations in this QM/MM study were carried out with density functional theory with the B3LYP functional and the lacvp* basis set. In the case of calculations concerning 3-8, the following atoms were constrained for both QM Region I and QM Region II: the backbone atoms of Ser402, Gly403, His404, the methylene atoms of Arg360 and Arg 490, H50 and H51 of the guanidine of Arg360, as well as H52 of HIE404. For the other input structures (1-2, 9-23), all of these atoms as well as the side chain atoms of Asp292 were constrained. These constraints were used to speed up convergence of the geometry optimization and follow the literature. As stated above, the entire Arg360 residue, which is next to Pro361, was included in the QM region, but the only parameterized cut for proline in QSite is along C-Cα; hence, the entire Pro361 would have had to be included. As a result, Pro361 was simplified to alanine following the example of Kravitz et al., and this alanine was constrained during the geometry optimizations. In the case of QM Region II, all of the atoms in the sequence Ala399-Pro395 were constrained except for the phenyl atoms (i.e., CH2-Ph) of Phe397. The MM region consisted of the remainder of the enzyme; the protein backbone was frozen during the MM optimizations. Furthermore, any MM atoms beyond 20 Å from vanadium were frozen. MM optimization was done with the OPLS_2005 force field. Solvent effects were modeled by neutralizing charged surface residues. The solvent accessible surface area (SASA) of each residue was determined by the method of Lee and Richards which is implemented in Bioluminate, a software of Schrodinger Corporation, and Bioluminate was used to determine the SASA of each residue. Any charged surface residue with a SASA of greater than 1 Å 2 was neutralized.