Luis Rodríguez-Santiago

Protonation of glycine, serine and cysteine. Conformations, proton affinities and intrinsic basicities

Abstract Proton affinities and gas-phase basicities of glycine, serine and cysteine have been computed using the three-parameter B3LYP density functional approach. For that, the geometry and vibrational frequencies of several conformations of neutral and protonated glycine, serine and cysteine have been explored. The preferred site for protonation in all aminoacids is the amino group. The lowest conformation always shows an intramolecular hydrogen bond between NH3+ and the carbonylic oxygen. For serine and cysteine, additional hydrogen bonds may be formed, the favored interaction being that in which the oxygen or sulfur atoms of the side chain interact, as proton acceptor, with NH3+. The computed B3LYP proton affinities and gas-phase basicities are in very good agreement with the known experimental data.

Mechanistic Insights into Ring-Closing Enyne Metathesis with the Second- Generation Grubbs-Hoveyda Catalyst: A DFT Study

The full catalytic process (precatalyst activation, propagating cycle and active-species interconversion) of the ring-closing enyne metathesis (RCEYM) reaction of 1-allyloxy-2-propyne with the Grubbs-Hoveyda complex as catalyst was studied by B3LYP density functional theory. Both the ene-then-yne and yne-then-ene pathways are considered and, for the productive catalytic cycle, the feasibility of the endo-yne-then-ene route is also explored. Calculations predict that the ene-then-yne and yne-then-ene pathways proceed through equivalent steps, the only major difference being the order in which they take place. In this way, all alkene metathesis processes studied here involve four steps: olefin coordination, cycloaddition, cycloreversion and olefin decoordination. Among them, the two more energetically demanding ones are the olefin coordination and decoordination steps. The reaction of the alkyne fragment consists of two steps: alkyne coordination and alkyne skeletal reorganization, the latter of which has the highest Gibbs energy barrier. Comparison between the ene-then-yne and yne-then-ene pathways shows that there is no clear energetic preference for either of the two processes, and thus both should be operative when unsubstituted enynes are involved. In addition, although the endo orientation is computed to be slightly disfavored, it is not ruled out for 1-allyloxy-2-propyne, and thus calculations seem to indicate that the exo versus endo selectivity is strongly influenced by the presence of substituents in the reagent.

Crystal structure of thioflavin-T and its binding to amyloid fibrils: insights at the molecular level

Combining X-ray data on thioflavin-T and theoretical calculations on its binding to a peptide model for Abeta(1-42) fibrils gives evidence of main stabilizing interactions, which influence the dihedral angle between the two moieties of thioflavin-T and thereby its fluorescence properties; these results shed new light on possible strategies for the design of dyes to bind amyloid fibrils more specifically.

Three dimensional models of Cu(2+)-Aβ(1-16) complexes from computational approaches.

Elucidation of the coordination of metal ions to Aβ is essential to understand their role in its aggregation and to rationally design new chelators with potential therapeutic applications in Alzheimer disease. Because of that, in the last 10 years several studies have focused their attention in determining the coordination properties of Cu(2+) interacting with Aβ. However, more important than characterizing the first coordination sphere of the metal is the determination of the whole Cu(2+)-Aβ structure. In this study, we combine homology modeling (HM) techniques with quantum mechanics based approaches (QM) to determine plausible three-dimensional models for Cu(2+)-Aβ(1-16) with three histidines in their coordination sphere. We considered both ε and δ coordination of histidines 6, 13, and 14 as well as the coordination of different possible candidates containing oxygen as fourth ligand (Asp1, Glu3, Asp7, Glu11, and CO(Ala2)). Among the 32 models that enclose COO(-), the lowest energy structures correspond to [O(E3),N(δ)(H6),N(ε)(H13),N(ε)(H14)] (1), [O(E3),N(δ)(H6),N(δ)(H13),N(δ)(H14)] (2), and [O(D7),N(ε)(H6),N(δ)(H13),N(δ)(H14)] (3). The most stable model containing CO(Ala2) as fourth ligand in the Cu(2+) coordination sphere is [O(c)(A2),N(ε)(H6),N(δ)(H13),N(ε)(H14)] (4). An estimation of the relative stability between Glu3 (1) and CO(Ala2) (4) coordinated complexes seems to indicate that the preference for the latter coordination may be due to solvent effects. The present results also show the relationship between the peptidic and metallic moieties in defining the overall geometry of the complex and illustrate that the final stability of the complexes results from a balance between the metal coordination site and amyloid folding upon complexation.

The Role of Exact Exchange in the Description of Cu2+−(H2O)n (n = 1−6) Complexes by Means of DFT Methods

This paper analyses the behavior of different density functionals in the description of the most stable structures of Cu(2+)-(H(2)O)(n) complexes (n = 1-6). From n = 3 to n = 6, different coordination numbers of the metal cation were considered. The structures and energies of the complexes were theoretically determined by means of density functional methods that include different amounts of exact exchange: the BLYP functional (0% of exact exchange), the B3LYP functional (20% of exact exchange), the MPWB1K functional (44% of exact exchange), and BHLYP functional (50% of exact exchange). In addition, CCSD(T) calculations with a large basis set were carried out. It has been found that the functionals with lesser amount of exact exchange, especially BLYP, fail to describe the relative energies between the different structures of each cluster because these functionals tend to overestimate the stability of low-coordinated structures. The inclusion of the exact exchange into the functional improves the results, those obtained with MPWB1K and BHLYP being in very good agreement with the CCSD(T) ones. This behavior is related to the poor description of the second ionization energy of Cu by pure functionals, which leads to a too delocalized spin density in the complex with GGA functionals.

Solvent-assisted catalysis in the enolization of acetaldehyde radical cation

Abstract The keto–enol isomerization of neutral and ionized acetaldehyde, both isolated and catalyzed by solvent molecules, has been studied using the B3LYP and MP2 levels of theory. Single-point calculations at the CCSD(T) level have also been performed. The results show that ionization favors the enolization of acetaldehyde, both thermodynamically and kinetically. Solvent molecules produce an important catalytic effect, especially for the methanol-solvated system, for which the transition state of the isomerization lies below the ground-state asymptote.

Gas Phase Intramolecular Proton Transfer in Cationized Glycine and Chlorine Substituted Derivatives (M–Gly, M=Na+, Mg2+, Cu+, Ni+, and Cu2+): Existence of Zwitterionic Structures?

The intramolecular proton transfer in cationized glycine and chlorine substituted derivatives with M = Na+, Mg2+, Ni+, Cu+, and Cu2+ has been studied with the three parameter B3LYP density functional method. The coordination of metal cations to the oxygens of the carboxylic group of glycine stabilizes the zwitterionic structure. For all monocations the intramolecular proton transfer occurs readily with small energy barriers (1-2 kcalmol(-1)). For the dication Mg2+ and Cu2+ systems, the zwitterionic structure becomes very stable. However, whereas for Mg2+, the proton transfer process takes place spontaneously, for Cu2+ the reaction occurs with an important energy barrier. The substitution of the hydrogens of the amino group by chlorine atoms decreases the basicity of nitrogen, which destabilizes the zwitterionic structure. For monosubstituted glycine complexed with Na+, the zwitterionic structure still exists as a minimum, but for disubstituted glycine no minimum appears for this structure. In contrast, for Mg2+ complexed to mono- and disubstituted glycine, the zwitterionic structure remains the only minimum, since the enhanced electrostatic interaction with the dication overcomes the destabilizing effect of the chlorine atoms.

Influence of the Side Chain in the Structure and Fragmentation of Amino Acids Radical Cations.

The conformational properties of ionized amino acids (Gly, Ala, Ser, Cys, Asp, Gln, Phe, Tyr, and His) have been theoretically analyzed using the hybrid B3LYP and the hybrid-meta MPWB1K functionals as well as with the post-Hartree Fock CCSD(T) level of theory. As a general trend, ionization is mainly localized at the -NH2 group, which becomes more planar and acidic, the intramolecular hydrogen bond in which -NH2 acts as proton donor being strengthened upon ionization. For this reason, the so-called conformer IV(+) becomes the most stable for nonaromatic amino acid radical cations. Aromatic amino acids do not follow this trend because ionization takes place mainly at the side chain. For these amino acids for which ionization of the side chain prevails over the -NH2 group, structures III(+) and II(+) become competitive. The Cα-X fragmentations of the ionized systems have also been studied. Among the different decompositions considered, the one that leads to the loss of COOH(•) is the most favorable one. Nevertheless, for aromatic amino acids fragmentations leading to R(•) or R(+) start being competitive. In fact, for His and Tyr, results indicate that the fragmentation leading to R(+) is the most favorable process.

Comparison of density functional and coupled cluster methods in the study of metal–ligand systems: Sc–CO2 and Cu–NO2

The structure, binding energies, and vibrational frequencies have been determined for the 1A1 state of the η2‐O,O coordination mode of Cu–NO2 and the 2A1 state of the η2‐O,O coordination mode of Sc–CO2. Calculations have been done using coupled cluster methods and methods based on the density functional theory. The results obtained show that all the levels of calculation lead to very similar equilibrium geometries and vibrational frequencies, while different results are obtained for the binding energy. For Sc–CO2 density functional methods overestimate the binding energy with respect to coupled cluster, while for Cu–NO2 the density functional binding energies are lower than the coupled cluster value. In both cases the inclusion of the exact Hartree–Fock exchange into the functional leads to an improvement of the density functional result. Our best estimates for the binding energies of Sc–CO2 and Cu–NO2 are 25 and 50 kcal mol−1, respectively.

3D structures and redox potentials of Cu2+-Aβ(1-16) complexes at different pH: a computational study.

Oxidative stress induced by redox-active metal cations such as Cu(2+) is a key event in the development of Alzheimers disease. A detailed knowledge of the structure of Cu(2+)-Aβ complex is thus important to get a better understanding of this critical process. In the present study, we use a computational approach that combines homology modeling with quantum-mechanics-based methods to determine plausible 3D structures of Cu(2+)-Aβ(1-16) complexes that enclose the different metal coordination spheres proposed experimentally at different pH values. With these models in hand, we determine their standard reduction potential (SRP) with the aim of getting new insights into the relation between the structure of these complexes and their redox behavior. Results show that in all cases copper reduction induces CObackbone decoordination, which, for distorted square planar structures in the oxidized state (Ia_δδ, IIa_εδε, IIa_εεε, and IIc_ε), leads to tricoordinated species. For the pentacoordinated structural candidate Ib_δε with Glu11 at the apical position, the reduction leads to a distorted tetrahedral structure. The present results highlight the importance of the nature of the ligands on the SRP. The computed values (with respect to the standard hydrogen electrode) for complexes enclosing negatively charged ligands in the coordination sphere (from -0.81 to -0.12 V) are significantly lower than those computed for models involving neutral ligands (from 0.19 to 0.28 V). Major geometry changes induced by reduction, on both the metal site and the peptide configuration, are discussed as well as their possible influence in the formation of reactive oxygen species.