This is an author version of the contribution published on:Questa

A comparative study of the metal−glycine bonding for the biologically relevant Cu+ and Cu2+ pair is presented. The structure and vibrational frequencies for several coordination modes of Cu+ and Cu2+ to glycine have been determined using the hybrid three-parameter B3LYP density functional approach. Single-point calculations have also been carried out at the modified coupled pair functional (MCPF) and single- and double- (triple) excitation coupled cluster (CCSD(T)) levels of theory and using larger basis sets. Calculations have shown that the metal−glycine bonding and the energy ordering of the different conformers are very different in Cu+-glycine than in Cu2+-glycine. Whereas for Cu+-glycine, the ground state structure is found to have a bidentated η2-N,O coordination in which Cu+ interacts with the nitrogen of the amino group and the carbonyl oxygen, the ground state structure of Cu2+-glycine is the η 2 -O,O (CO2 -) one, derived from the interaction of the metal cation with the CO2 - terminus of the zwitterionic glycine. In this case, the results seem to indicate that glycine acquires an important radical character that changes the relative metal affinities of the different basic sites, which favors the interaction of the metal cation with the CO2 group compared with other coordinations.

Correlated calculations show the proton-transferred OH−H3O+ isomer to be the ground-state structure of the (H2O)2 + dimer ion, with the C 2 h hemibond structure being ca. 8 kcal/mol less stable. Modern density functionals however favor the hemibond structure, overestimating the strength of the three-electron bond by ca. 17 kcal/mol. The wrong prediction of the relative stability of the two isomers is attributed to overestimation by the exchange functionals of the self-interaction part of the exchange energy in the hemibond ion due to its delocalized electron hole. It is cautioned that this erroneous behavior of the density functionals for exchange, if unrecognized, may lead to wrong predictions for ground-state structures of systems with a three-electron bond.

The structure and binding energies are determined for many of the M(H2O)+n and M(H2O)2+n species, for n=1–3 and M=Mg, Ca, or Sr. The trends are explained in terms of metal sp or sdσ hybridization and core polarization. The M(NH3)+n systems, with M=Mg or Sr, are also studied. For the positive ions, the low-lying excited states are also studied and compared with experiment. The calculations suggest an alternative interpretation of the SrNH+3 spectrum.

Single and double proton-transfer reactions in Watson−Crick Guanine−Cytosine (GC) and Adenine−Thymine (AT) radical cations have been studied using the hybrid density functional B3LYP method. Calibration calculations for the formamidine−formamide dimer, a model system of AT, have shown that B3LYP compares well to the high level ab initio correlated method CCSD(T), both for the neutral and cationic systems. The single proton-transfer reaction is favorable in both the GC and AT radical cations; it takes place from the ionized monomer (guanine and adenine, respectively), which increases its acidity, to the neutral fragment. For the two systems, GC and AT, the nonproton transferred and single proton transferred structures are almost degenerate (ΔE = 1.2 kcal/mol), and the process presents low energy barriers (4.3 kcal/mol for GC and 1.6 kcal/mol for AT). The double proton-transfer reaction is less favorable than the single one, in contrast to what is observed for the neutral systems. The relative stability of the different structures can be understood considering two factors:  the relative stability of the asymptotes from which they derive and the number and sequence of the strong and weak hydrogen bonds formed. For the same number of strong short hydrogen bonds, the most stable structures are those in which the strong H-bonds are neighbors. Based on these considerations, a prediction for other pairings is reported.

Realistic models of amorphous silica surfaces with different degrees of hydroxylation and of the MCM‐41 mesoporous material are determined ab initio at the B3LYP level. Comparison with structural and vibrational experimental data confirms the validity of these models, which will be very useful for future computational studies.

Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.

The coordination of carbon dioxide to first transition row metal cations and the insertion reaction of the metal into one CO bond of carbon dioxide have been studied theoretically. The geometry and the vibrational frequencies of the M+−CO2 and OM+CO structures have been determined using the hybrid three-parameter B3LYP density functional approach. Binding energies have also been determined at the CCSD(T) level using large basis sets. The linear end-on M+−OCO structure is the most favorable coordination for CO2, due to the electrostatic nature of the bonding. In the inserted OM+CO structures, the bonding arises from the electrostatic interaction between the ground state of OM+ and CO. For the early transition metals (Sc+, Ti+, and V+), the insertion reaction is exothermic and the inserted OM+CO structure is more stable than the linear M+−OCO isomer, because of the very strong MO+ bond that is formed.