Mo-aminoacid Complexes as Analogs for Mo- based Enzymes: A DFT Approach S. Sabiah An Overview Introduction Importance of Molybdo-enzymes Focus of Present Study Methodology-DFT Mo-Aminoacid complexes and their anionic analogs Relative Redox Energy of the systems Mo-Substrate intermediates Conclusions Mo-based Enzymes in Biology 3 3 R. L. McNaughton, S. Mondal, V. N. Nemykin, P. Basu, M. L. Kirk, Inorg. Chem. 2005, 44, 8216 Reduction of DMSO to DMS Oxidation of sulfite to sulfate Oxidation of xanthine to uric acid Indirectly involve in the global cycling of sulphur, nitrogen and carbon XO has gained attention regarding its active site structure and catalytic mechanism is still the subject of controversy EXAFS studies of oxidized [Mo(VI)] and reduced [Mo(IV)] core structures Unique sulfido (=S), oxo (=O) liands with hydroxyl (OH) and dithiopterin cofactor (dpt) Such Mo(VI) core structures (cis Mo=S, =O) are rare Recent theoretical report on the catalytic mechanism of XO, reveals that the glutamic aminoacid in the surrounding environment plays crucial role Xanthine Oxidase Amano, T.; Ochi, N.; Sato, H.; Sakaki, S. J. Am. Chem. Soc.; 2007, 129, [Mo 3 ( O) 2 ( -O 2 CCH 3 ) 6 (H 2 O) 3 ] 2+ Annu. Rep. Prog. Chem., Sect. A: Inorg. Chem., 2007, 103, Molybdocene complex-Antitumor activity Mo-oxo complex-architectures 5 5 But still Mo(VI) complexes with aminoacid are scant in literature. Focus of Present Study 6 6 Try to optimize the hypothesized Mo(VI) aminoacid complexes with sulfido (=S) and oxo (=O) ligands Mo(VI)SO(A)(dt), (dt is dithiolene unit as model for dithiopterin cofactor (S-CH=CH-S) Study the one electron reduced species Estimate the relative redox energies by Born-Heber cycle As a model substrate of xanthine, the catalytic oxidation of pyrimidin-4-ol (Py-4) to pyrimidin-2,4-diol (Py-2,4) Optimize the possible Mo(V) and Mo(IV)-substrate intermediates 7 7 N. Allinger, Encyclopedia of Computational Chemistry, 1997, 1-5, The energy, E, is a function of the atomic positions, R, of all the atoms in the system, is calculated as a sum of bonded, terms Ebonded, which describe the bonds, angles and bond rotations in a molecule, and a sum of external or nonbonded terms, Enon-bonded The E bonded term is a sum of three terms: which correspond to three types of atom movement: Computational Basics H = E Schroedinger eqn DFT calculations, including geometry optimization and NBO analysis, were performed using a hybrid functional B3LYP as implemented in Gaussian The LANL2DZ basis set and effective core potential were used for molybdenum. When the optimization was tried for calculation with mixed basis set with LANL2DZ for Mo and 6-31G(d) for C, N, O and S, resulted in convergence failure. Hence the calculations have been carried out only with LANL2DZ for all Mo analogs However, for the simple organic substrates, pyrimidin-4-ol (Py-4) and pyrimidin-2,4-diol (Py-2,4) the usual 6-31G(d) basis sets were employed Calculation for vibrational frequencies was performed alongside each geometry optimization to ensure the stability of the ground state as denoted by the absence of imaginary frequencies. Methodology Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. 1988, 37, 9 9 1 trial 84 th trial Geometry Optimization of Mo(OMe) 6 Inorg. Chem. 2001, 40, 3815 Total electron density mapSimulated IR spectrum 10 11 Mo-Aminoacid Complexes 1. As a first step for the optimization of aminoacid complexes, a structurally known neutral Mo(VI) complex, [MoO2(L-CysOMe)2], 1 with substituted cystein aminoacid was considered and optimized with B3LYP/DFT calculation. Chemdraw representation of [Mo(O 2 )(L-Cys-OMe) 2 ], 1 Buchanan, I.; Minelli, M. Ashby, M. T.; King, T. J.; Enemark, J. H.; Garner, C. D. Inorg. Chem., 1984, 23, 495 Preliminary Studies Bond distances ()Bond angles ( o ) XRDDFTXRDDFT Mo=O = , 1.742O-Mo-O'= Mo-S = , 2.513S-Mo-S' = Mo-N = , 2.398N-Mo-N' = S-C = , 1.897O-Mo-N' = , N-C = , 1.492O-Mo-N = , 84.5 C-C= , 1.544O-Mo-S = , C=O = , 1.239O-Mo-S' = , 91.5 C-O = , 1.383N-Mo-S = , 77.4 O-CH3 = , 1.479N-Mo-S' = , 81.5 Table 1. Comparison of bond distances () and angles (o) of [Mo(O 2 )(L-Cys-OMe) 2 ] cis-dioxo cis-diamino trans disulfide coordination around Mo 12 2. [Mo(VI)(O)(S)(dt)], 2 and [Mo(VI)(O)(S)(OH)(dt)] -1, 3 have been optimized as the active site models for XO with dithiolene unit (dt, S-CH=CH-S). [Mo(VI)(O)(S)(dt)], 2[Mo(VI)(O)(S)(OH)(dt)] -1, 3 XNO-Active site models 13 Mo-L XO, 2 XO-OH, 3 EXAFSThis studyADFEXAFSThis studyADF Mo=S Mo=O Mo-S Mo-S Mo-OH Table 2. Comparison of Mo-L distances for XO models 2 and 3 with EXAFS and ADF * * Seisenbaeva, G. A.; Kloo, L.; Werndrup, P.; Kessler, V. G. Inorg. Chem., 2001, 40, 3. Having known that DFT theory gives comparable results for complexes 1, 2 & 3, the Mo complexes with aminoacids, [Mo(VI)(S)(O)(A)(dt)], 4-8 [(A= Glycine, 4; Alanine, 5; Valin, 6; Cystein, 7; Histidine, 8 and their reduced analogs, [Mo(VI)(S)(O)(A)(dt)] -1, 9-13 have been considered. The optimized Oh geometry of Mo-gly complex, 4 Optimization of Mo-aminoacid complexes cis-oxo, sulfido cis-amino, carboxylato cis disulfide coordination around Mo stabilization energy is in the range of to a.u. The addition of aminoacid stabilizes the molecules compared to isolated free atoms 15 M-L distances () M-LMo-GlyMo-AlaMo-ValMo- Cys Mo- Hist Mo=S2.24 Mo=O1.73 Mo-S Mo-S Mo-N Mo-O L-Mo-L ( ) S-Mo-O oxo N-Mo- O acid S dt -Mo-S dt S-Mo-S dt N-Mo-S dt O-Mo- O acid Table 3. Comparison of selected bond parameters of Mo-aminoacid complexes The Mo=O distances are ~1.73 and much deviated from the hydroxyl coordinated molybdenum complexes (Mo-O~ ) no covalent interactions between the metal and sulfur or ring nitrogen of Cyst and Hist cis-dioxo widens up to an angle of ~108 (in complex 1) and in the case of Mo-aminoacid complexes with O-Mo-S up to . The small differences in angles are due to the constraints of the extra chelate ring with bidentate dithiolate and aminoacid ligands 16 Table 4. Comparison of calculated M-L distances for reduced Mo-aminoacid analogs M-LMo-Gly anion Mo-Ala anion Mo-Val anion Mo-Cys anion Mo-Hist anion Mo=S Mo=O1.73 Mo-S Mo-S Mo-N Mo-O Optimization of Mo-aminoacid anionic analogs Mo-S and Mo=S distances are longer for anionic analogs than their parent structures due to electronic delocalization around sulfur atoms 17 Vibrational Analysis The simulated IR spectrum of Mo-Gly complex, 4 IR vibratonsMo- Gly Mo- Ala Mo-ValMo- Cys Mo-Hist -NH 2 symmetric asymmetric bending CH=CH symmetric asymmetric COO asymmetric C-O CH, CH 2, CH , , , Table 5. selected IR vibrations 18 Population Analysis The HOMO and LUMO of Mo-Gly complex, 4 The HOMO consists of