This study presents an implementation of the protein-ligand docking program GOLD and a generalizable method to predict the binding site and orientation of potential vanadium drugs. Particularly, theoretical methods were applied to the study of the interaction of two VO complexes with antidiabetic activity, [VO(pic)(HO)] and [VO(ma)(HO)], where pic is picolinate and ma is maltolate, with lysozyme (Lyz) for which electron paramagnetic resonance spectroscopy suggests the binding of the moieties VO(pic) and VO(ma) through a carboxylate group of an amino acid residue (Asp or Glu). The work is divided in three parts: (1) the generation of a new series of parameters in GOLD program for vanadium compounds and the validation of the method on five X-ray structures of VO and V species bound to proteins; (2) the prediction of the binding site and enantiomeric preference of [VO(pic)(HO)] to lysozyme, for which the X-ray diffraction analysis displays the interaction of a unique isomer (i.e., OC-6-23-Δ) through Asp52 residue, and the subsequent refinement of the results with quantum mechanics/molecular mechanics methods; (3) the application of the same approach to the interaction of [VO(ma)(HO)] with lysozyme. The results show that convenient implementation of protein-ligand docking programs allows for satisfactorily reproducing X-ray structures of metal complexes that interact with only one coordination site with proteins and predicting with blind procedures relevant low-energy binding modes. The results also demonstrate that the combination of docking methods with spectroscopic data could represent a new tool to predict (metal complex)-protein interactions and have a general applicability in this field, including for paramagnetic species.

The behaviour of the systems formed by VO(2+), 2-hydroxypyridine-N-oxide (Hhpo) and 2-mercaptopyridine-N-oxide (Hmpo) was studied both in solution and in the solid state through the combined application of spectroscopic (EPR and UV-Vis spectroscopy) and DFT methods. The geometry of solid bis-chelated complexes [VOL(2)], with L = hpo and mpo, is square pyramidal, but it can change to cis-[VOL(2)S], where S is a solvent molecule, when these are dissolved in a coordinating solvent. The equilibrium between the square pyramidal and cis-octahedral forms is strongly affected by solvent and temperature. At room temperature, the predominant species is [VOL(2)], which gives a pink colour to the solutions; at lower temperatures, the equilibrium is shifted--partially or completely--toward the formation of cis-[VOL(2)S], which is green. In an acidic environment and in the presence of an excess of ligand, [VOL(2)] can transform into the tris-chelated complex [VL(3)](+), in which vanadium loses the oxido ligand and adopts a hexa-coordinated geometry intermediate between octahedral and trigonal prismatic. 1-Methylimidazole (1-MeIm), which represents a model for His-N coordination, forms mixed complexes with stoichiometry cis-[VOL(2)(1-MeIm)], occupying an equatorial position. In the ternary systems VO(2+)-Hhpo-hTf and VO(2+)-Hmpo-hTf at room temperature and pH 7.4, besides (VO)hTf and (VO)(2)hTf, the mixed species cis-VO(hpo)(2)(hTf) and VO(mpo)(hTf) are observed, with the equatorial binding of an accessible histidine residue. Finally, the contribution of the N-oxide group to (51)V A(z) and A(iso) hyperfine coupling constants, which can be important in the characterisation of similar species, is discussed.

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Density functional theory (DFT) calculations of the (51)V hyperfine coupling (HFC) tensor A have been completed for 20 "bare" V(IV) complexes with different donor sets, electric charges, and coordination geometries. Calculations were performed with ORCA and Gaussian software, using functionals BP86, TPSS0, B1LYP, PBE0, B3LYP, B3P, B3PW, O3LYP, BHandHLYP, BHandH, and B2PLYP. Among the basis sets, 6-311g(d,p), 6-311++g(d,p), VTZ, cc-pVTZ, def2-TZVPP, and the "core properties" CP(PPP) were tested. The experimental Aiso and Ai (where i = x or z, depending on the geometry and electronic structure of V(IV) complex) were compared with the values calculated by DFT methods. The results indicated that, based on the mean absolute percentage deviation (MAPD), the best functional to predict Aiso or Ai is the double hybrid B2PLYP. With this functional and the basis set VTZ, it is possible to predict the Aiso and Az of the EPR spectrum of amavadin with deviations of -1.1% and -2.0% from the experimental values. The results allowed us to divide the spectra of nonoxido V(IV) compounds in three types-called "type 1", "type 2", and "type 3", characterized by different composition of the singly occupied molecular orbital (SOMO) and relationship between the values of Ax, Ay, and Az. For "type 1" spectra, Az ≫ Ax ≈ Ay and Az is in the range of (135-155) × 10(-4) cm(-1); for "type 2" spectra, Ax ≈ Ay ≫ Az and Ax ≈ Ay are in the range of (90-120) × 10(-4) cm(-1); and for the intermediate spectra of "type 3", Az > Ay > Ax or Ax > Ay > Az, with Az or Ax values in the range of (120-135) × 10(-4) cm(-1). The electronic structure of the V(IV) species was also discussed, and the results showed that the values of Ax or Az are correlated with the percent contribution of V-dxy orbital in the SOMO. Similarly to V(IV)O species, for amavadin the SOMO is based mainly on the V-dxy orbital, and this accounts for the large experimental value of Az (153 × 10(-4) cm(-1)).

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