Search

This paper investigates the esterase activity of minimalist amyloid fibers composed of short seven‐residue peptides, IHIHIHI (IH7) and IHIHIQI (IH7Q), with a particular focus on the role of the sixth residue position within the peptide sequence. Through computational simulations and analyses, we explore the molecular mechanisms underlying catalysis in these amyloid‐based enzymes. Contrary to initial hypotheses, our study reveals that the twist angle of the fiber, and thus the catalytic site's environment, is not notably affected by the sixth residue. Instead, the sixth residue interacts with the p‐nitrophenylacetate (pNPA) substrate, particularly through its −NO2 group, potentially enhancing catalysis. Quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction mechanism suggest that the polarizing effect of glutamine enhances catalytic activity by forming a stabilizing network of hydrogen bonds with pNPA, leading to lower energy barriers and a more exergonic reaction. Our findings provide valuable insights into the intricate interplay between peptide sequence, structural arrangement, and catalytic function in amyloid‐based enzymes, offering potentially valuable information for the design and optimization of biomimetic catalysts. [ABSTRACT FROM AUTHOR]

Abstract: The reactions between Cu+ and the four natural aromatic amino acids (AAarom =Phe, Tyr, Trp and His) have been investigated by means of electrospray ionization mass spectrometry. Metal cation complexes ([Cu AAarom]+) were formed in the electrospray source and collision-induced fragmentations of the most abundant isotopic form, [63Cu AAarom]+, were studied for each amino acid. The same fragmentation pattern is observed for all the amino acids, the most important peak corresponding in all cases to the loss of CH2O2. Among the four aromatic amino acids, the [Cu Phe]+ complex was selected for a computational study of the potential energy surface. Several mechanisms were studied at the B3LYP level and most of the observed fragmentations start with the metal cation insertion into the Ce bond or into the C the amino acid. [Copyright &y& Elsevier]

Iridium oxide is a highly efficient catalyst for the oxygen evolution reaction, whose large-scale application requires decreasing the metal content. This is achieved using small nanoparticles. The knowledge of the water-IrO 2 nanoparticle interface is of high importance to understand the IrO 2 behavior as electrocatalyst in aqueous solutions. In this contribution, DFT (PBE-D2) calculations and AIMD simulations on IrO 2 nanoparticle models of different sizes ((IrO 2 ) 33 and (IrO 2 ) 115 ) are performed. Results show that two key factors determine the H 2 O adsorption energy and the preferred adsorption structure (molecular or dissociated water): metal coordination and hydrogen bonding with oxygen bridge atoms of the IrO 2 surface. Regarding metal coordination, and since the tetragonal distortion existing in IrO 2 is retained on the nanoparticle models, the adsorption at iridium axial vacant sites implies stronger Ir-H 2 O interactions, which favors water dissociation. In contrast, Ir-H 2 O interaction at equatorial vacant sites is weaker and thus the relative stability of molecular and dissociated forms becomes similar. Hydrogen bonding increases adsorption energy and favors water dissociation. Thus, tip and corner sites of the nanoparticle, with no oxygen bridge atoms nearby, exhibit the smallest adsorption energies and a preference for the molecular form. Overall, the presence of rather isolated tip and corner sites in the nanoparticle leads to lower adsorption energies and a smaller degree of water dissociation when compared with extended surfaces.

This article provides the computational prediction of the atomistic architectures resulting from self-assembly of the polar heptapeptide sequences NYNYNYN, SYSYSYS and GYGYGYG. Using a combination of molecular dynamics and a newly developed tool for non-covalent interaction analysis, we uncover the properties of a new class of bionanomaterials, including hydrogen-bonded polar zippers, and the relationship between peptide composition, fibril geometry and weak interaction networks. Our results, corroborated by experimental observations, provide the basis for the rational design of prion-inspired nanomaterials., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Metallophilicity is an essential concept that builds upon the attraction between closed shell metal ions. We report on the [M 2 (bisNHC) 2 ] 2+ (M=Au I , Ag I ; NHC=N-heterocyclic carbene) systems, which display almost identical features in the solid state. However, in solution the Au 2 cation exhibits a significantly higher degree of rigidity owed to the stronger character of the aurophilic interactions. Both Au 2 and Ag 2 cationic constructs are able to accommodate Ag + ions via M-M interactions, despite their inherent Coulombic repulsion. When electrostatic repulsion between host and guest is partially diminished, M-M distances are substantially shortened. Quantum chemical calculations estimate intermetallic bond orders up to 0.2. Although at the limit of (or beyond) the van der Waals radii, metallophilic interactions are responsible for their behavior in solution., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Understanding metal oxide MO 2 (M = Ti, Ru, and Ir)-water interfaces is essential to assess the catalytic behavior of these materials. The present study analyzes the H 2 O-MO 2 interactions at the most abundant (110) and (011) surfaces, at two different water coverages: isolated water molecules and full monolayer, by means of Perdew-Burke-Ernzerhof-D2 static calculations and ab initio molecular dynamics (AIMD) simulations. Results indicate that adsorption preferably occurs in its molecular form on (110)-TiO 2 and in its dissociative form on (110)-RuO 2 and (110)-IrO 2 . The opposite trend is observed at the (011) facet. This different behavior is related to the kind of octahedral distortion observed in the bulk of these materials (tetragonal elongation for TiO 2 and tetragonal compression for RuO 2 and IrO 2 ) and to the different nature of the vacant sites created, axial on (110) and equatorial on (011). For the monolayer, additional effects such as cooperative H-bond interactions and cooperative adsorption come into play in determining the degree of deprotonation. For TiO 2 , AIMD indicates that the water monolayer is fully undissociated at both (110) and (011) surfaces, whereas for RuO 2 , water monolayer exhibits a 50% dissociation, the formation of H 3 O 2 - motifs being essential. Finally, on (110)-IrO 2 , the main monolayer configuration is the fully dissociated one, whereas on (011)-IrO 2 , it exhibits a degree of dissociation that ranges between 50 and 75%. Overall, the present study shows that the degree of water dissociation results from a delicate balance between the H 2 O-MO 2 intrinsic interaction and cooperative hydrogen bonding and adsorption effects., Competing Interests: The authors declare no competing financial interest.

Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2(5 H)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all- cis 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups.

Senile plaques are extracellular deposits found in patients with Alzheimer's Disease (AD) and are mainly formed by insoluble fibrils of β-amyloid (Aβ) peptides. The mechanistic details about how AD develops are not fully understood yet, but metals such as Cu, Zn, or Fe are proposed to have a non-innocent role. Many studies have also linked the non biological metal aluminum with AD, a species whose concentration in the environment and food has been constantly increasing since the industrial revolution. Gaining a molecular picture of how Al(iii) interacts with an Aβ peptide is of fundamental interest to improve understanding of the many variables in the evolution of AD. So far, no consensus has been reached on how this metal interacts with Aβ, partially due to the experimental complexity of detecting and quantifying the resulting Al(iii)-Aβ complexes. Computational chemistry arises as a powerful alternative to investigate how Al(iii) can interact with Aβ peptides, as suitable strategies could shed light on the metal-peptide description at the molecular level. However, the absence of any reliable template that could be used for the modeling of the metallopeptide structure makes computational insight extremely difficult. Here, we present a novel strategy to generate accurate 3D models of the Al(iii)-Aβ complexes, which still circumvents first principles simulations of metal binding to peptides of Aβ. The key to this approach lies in the identification of experimental structures of the isolated peptide that are favourably pre-organized for the binding of a given metal in configurations of the first coordination sphere that were previously identified as the most stable with amino acid models. This approach solves the problem of the absence of clear structural templates for novel metallopeptide constructs. The posterior refinement of the structures via QM/MM and MD calculations allows us to provide, for the first time, physically sound models for Al(iii)-Aβ complexes with a 1 : 1 stoichiometry, where up to three carboxylic groups are involved in the metal binding, with a clear preference towards Glu3, Asp7, and Glu11.

The coordination chemistry of the antitumor agent cisplatin and related complexes with DNA and its constituents, that is, the nucleobases, appears to be dominated by 1:1 and 1:2 adducts of the types cis-[Pta2 (nucleobase)X] and cis-[Pta2 (nucleobase)2 ] (a=NH3 or amine; a2 =diamine or diimine; X=Cl, OH or OH2 ). Here, we have studied the interactions of the putative 1:1 adducts cis-[Pta2 (1-MeC-N3)(OH2 )](2+) (with a=NH3 , a2 =2,2'-bpy (2,2'-bipyridine), 1-MeC=model nucleobase 1-methylcytosine) with additional cis-[Pt(NH3 )2 (OH2 )2 ](2+) or its kinetically superior analogues [Pd(en)(OH2 )2 ](2+) (en=ethylenediamine) and [Pd(2,2'-bpy)(OH2 )2 ](2+) . Depending upon the conditions applied different compounds of different nuclearity are formed. Without exception they represent condensation products of the components, containing μ-1-MeC-H , μ-OH(-) , as well as μ-NH2 (-) bridges. In the presence of Ag(+) ions, the isolated products in several cases display additionally Pt→Ag dative bonds. On the basis of the cytosine-containing structures established by X-ray crystallography, it is proposed that any of the feasible initial 1:1 nucleobase adducts of cisplatin could form dinuclear Pt complexes upon reaction with additional hydrolyzed cisplatin, thereby generating nucleobase adducts other than the presently established ones. Two findings appear to be of particular significance: First, hydrolyzed cisplatin can have a moderately accelerating effect on the formation of a secondary nucleobase product. Second, NH3 ligands of the cisplatin moiety can be converted into bridging amido ligands following condensation with the diaqua species of cisplatin., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We investigate, by means of density-functional theory, the binding of dioxygen to Cu(I)-amyloid β (Aβ), one of the first steps in the oxidation of ascorbate by dioxygen. Cu, Aβ, ascorbate and dioxygen are all present in the synapse during neurodegeneration, when the above species can trigger an irreversible oxidative stress inducing the eventual death of neurons. The binding of dioxygen to Cu(I) is possible and its role in dioxygen activation of Cu ligands and of residues in the first coordination sphere is described in atomic detail. Dioxygen is activated when a micro-environment suitable for a square-planar Cu(2+) coordination is present and a negatively charged group like Asp 1 carboxylate takes part in the Cu coordination anti to O2.

Several lines of evidence supporting the role of metal ions in amyloid aggregation, one of the hallmarks of Alzheimer's disease (AD), have turned metal ion chelation into a promising therapeutic treatment. The design of efficient chelating ligands requires proper knowledge of the electronic and molecular structure of the complexes formed, including their hydration properties. Among various potential chelators, clioquinol (5-chloro-7-iodo-8-hydroxyquinoline, CQH) has been evaluated with relative success in in vitro experiments and even in phase 2 clinical trials. Clioquinol interacts with Zn(ii) to lead to a binary metal/ligand 1 : 2 stoichiometric complex in which the phenolic group of CQH is deprotonated, resulting in Zn(CQ)2 neutral complexes, to which additional water molecules may coordinate. In the present work, the coordinative properties of clioquinol in aqueous solution have been analyzed by means of static, minimal cluster based DFT calculations and explicit solvent ab initio molecular dynamics simulations. Results from static calculations accounting for solvent effects by means of polarized continuum models suggest that the preferred metal coordination environment is tetrahedral Zn(CQ)2, whereas ab initio molecular dynamics simulations point to quasi degenerate penta Zn(CQ)2(H2O) and hexa Zn(CQ)2(H2O)2 coordinated complexes. The possible reasons for these discrepant results are discussed.

Oxidative stress induced by redox-active metal cations such as Cu(2+) is a key event in the development of Alzheimer's 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.

Of the numerous ways in which two adenine and two guanines (N9 positions blocked in each) can be cross-linked by three linear metal moieties such as trans-a2 Pt(II) (with a=NH3 or MeNH2 ) to produce open metalated purine quartets with exclusive metal coordination through N1 and N7 sites, one linkage isomer was studied in detail. The isomer trans,trans,trans-[{Pt(NH3 )2 (N7-9-EtA-N1)2 }{Pt(MeNH2 )2 (N7-9-MeGH)}2 ][(ClO4 )6 ]⋅3H2 O (1) (with 9-EtA=9-ethyladenine and 9-MeGH=9-methylguanine) was crystallized from water and found to adopt a flat Z-shape in the solid state as far as the trinuclear cation is concerned. In the presence of excess 9-MeGH, a meander-like construct, trans,trans,trans-[{Pt(NH3 )2 (N7-9-EtA-N1)2 }{Pt(MeNH2 )2 (N7-9-MeGH)2 }][(ClO4 )6 ]⋅[(9-MeGH)2 ]⋅7 H2 O (2) is formed, in which the two extra 9-MeGH nucleobases are hydrogen bonded to the two terminal platinated guanine ligands of 1. Compound 1, and likewise the analogous complex 1 a (with NH3 ligands only), undergo loss of an ammonia ligand and formation of NH4 (+) when dissolved in [D6 ]DMSO. From the analogy between the behavior of 1 and 1 a it is concluded that a NH3 ligand from the central Pt atom is lost. Addition of 1-methylcytosine (1-MeC) to such a DMSO solution reveals coordination of 1-MeC to the central Pt. In an analogous manner, 9-MeGH can coordinate to the central Pt in [D6 ]DMSO. It is proposed that the proton responsible for formation of NH4 (+) is from one of the exocyclic amino groups of the two adenine bases, and furthermore, that this process is accompanied by a conformational change of the cation from Z-form to U-form. DFT calculations confirm the proposed mechanism and shed light on possible pathways of this process. Calculations show that rotational isomerism is not kinetically hindered and that it would preferably occur previous to the displacement of NH3 by DMSO. This displacement is the most energetically costly step, but it is compensated by the proton transfer to NH3 and formation of U(-H(+) ) species, which exhibits an intramolecular hydrogen bond between the deprotonated N6H(-) of one adenine and the N6H2 group of the other adenine. Finally the question is examined, how metal cross-linking patterns in closed metallacyclic quartets containing two adenine and two guanine nucleobases influence the overall shape (square, rectangle, trapezoid) and the planarity of a metalated purine quartet., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

DFT (B3LYP-D) calculations have been used to better understand the origin of the recovered Hoveyda-Grubbs derivative catalysts after ring-closing diene or enyne metathesis reactions. For that, we have considered the activation process of five different Hoveyda-Grubbs precursors in the reaction with models of usual diene and enyne reactants as well as the potential precursor regeneration through the release/return mechanism. The results show that, regardless of the nature of the initial precursor, the activation process needs to overcome relatively high energy barriers, which is in agreement with a relatively slow process. The precursor regeneration process is in all cases exergonic and it presents low energy barriers, particularly when compared to those of the activation process. This indicates that the precursor regeneration should always be feasible, unlike the moderate recoveries sometimes observed experimentally, which suggests that other competitive processes that hinder recovery should take place. Indeed, calculations presented in this work show that the reactions between the more abundant olefinic products and the active carbenes usually require lower energy barriers than those that regenerate the initial precatalyst, which could prevent precursor regeneration. On the other hand, varying the precursor concentration with time obtained from the computed energy barriers shows that, under the reaction conditions, the precursor activation is incomplete, thereby suggesting that the origin of the recovered catalyst probably arises from incomplete precursor activation., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Thioflavin-T (ThT) is one of the most widely used dyes for staining and identifying amyloid fibrils, which share a common parallel in register β-sheet structure. Unfortunately, ThT is a charged molecule, which limits its ability to cross the blood brain barrier and its use as an efficient dye for in vivo detection of amyloid fibrils. For this reason, several uncharged ThT derivatives have been designed and their binding properties to Aβ fibrils studied by fluorescence assays. However, there are still many unknowns on the binding mechanism and the role of noncovalent interactions on the affinity of these ligands toward β-sheet structures. The present contribution analyzes the binding of ThT (1) and neutral ThT derivatives (2-7) to a β-sheet model by means of quantum chemical B3LYP-D calculations and including solvent effects with the continuum CPCM method. Results show that, in all cases, ligand binding is mainly driven by dispersion interactions. In addition, ligands with -NH groups display hydrogen bond interactions with CO groups of the peptide strand, increasing the intrinsic affinity toward the β-sheet surface. Solvent effects notably reduce the affinity of charged ThT, as compared to neutral systems, due to its larger solvation energy. As a result, neutral derivatives display significantly higher affinities than ThT in solution, in agreement with experimental observations. Analysis of the hydrogen bonding network of the β-sheet structure indicates that stacking interactions upon ligand binding induce a shortening of interstrand hydrogen bonding, suggesting a strengthening of the β-sheet.

Iron is one of the most abundant metals found in senile plaques of post mortem patients with Alzheimer's disease. However, the interaction mode between iron ions and β-amyloid peptide as well as their precise affinity is unknown. In this study we apply ab initio computational methodology to calculate binding energies of Fe(2+/3+) with the His13-His14 sequence of Aβ, as well as other important ligands such as His6 and Tyr10. Calculations were carried out at the "MP2/6-311+G(2df,2p)"//B3LYP/6-31+G(d) level of theory and solvent effects included by the IEFPCM procedure. Several reaction paths for the binding of imidazole, phenol, and the His13-His14 fragment (modeled by N-(2-(1H-imidazol-4-yl)ethyl)-3-(1H-imidazol-4-yl)propanamide) were sequentially explored. The results show that the most stable complexes containing His13-His14 and phenolate of Tyr10 are the pentacoordinated [Fe(2+)(O-HisHis)(PhO(-))(H(2)O)](+) and [Fe(3+)(N-HisHis)(PhO(-))(H(2)O)](+) compounds and that simultaneous coordination of tyrosine and His13-His14 to Fe(2+/3+) is thermodynamically favorable in water at physiological pH. Computed Raman spectra confirm the conclusion obtained by Miura et al. ( Biochemistry 2000 , 39 , 7024 ) that tyrosine is coordinated to Fe(3+) but do not exclude coordination of imidazoles. Finally, calculations of standard reduction potentials indicate that phenol coordination reduces the redox activity of the iron/Aβ complexes.

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 preparation and X-ray crystal structure analysis of {trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)]}⋅{3 K(2)[Pt(CN)(4)]}⋅6 H(2)O (3 a) (with 9-MeG being the anion of 9-methylguanine, 9-MeGH) are reported. The title compound was obtained by treating [Pt(dien)(9-MeGH-N7)](2+) (1; dien=diethylenetriamine) with trans-[Pt(MeNH(2))(2)(H(2)O)(2)](2+) at pH 9.6, 60 °C, and subsequent removal of the [(dien)Pt(II)] entities by treatment with an excess amount of KCN, which converts the latter to [Pt(CN)(4)](2-). Cocrystallization of K(2)[Pt(CN)(4)] with trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)] is a consequence of the increase in basicity of the guanine ligand following its deprotonation and Pt coordination at N1. This increase in basicity is reflected in the pK(a) values of trans-[Pt(MeNH(2))(2)(9-MeGH-N1)(2)](2+) (4.4±0.1 and 3.3±0.4). The crystal structure of 3 a reveals rare (N7,O6 chelate) and unconventional (N2,C2,N3) binding patterns of K(+) to the guaninato ligands. DFT calculations confirm that K(+) binding to the sugar edge of guanine for a N1-platinated guanine anion is a realistic option, thus ruling against a simple packing effect in the solid-state structure of 3 a. The linkage isomer of 3 a, trans-[Pt(MeNH(2))(2)(9-MeG-N7)(2)] (6 a) has likewise been isolated, and its acid-base properties determined. Compound 6 a is more basic than 3 a by more than 4 log units. Binding of metal entities to the N7 positions of 9-MeG in 3 a has been studied in detail for [(NH(3))(3)Pt(II)], trans-[(NH(3))(2)Pt(II)], and [(en)Pd(II)] (en=ethylenediamine) by using (1)H NMR spectroscopy. Without exception, binding of the second metal takes place at N7, but formation of a molecular guanine square with trans-[(Me(2)NH(2))Pt(II)] cross-linking N1 positions and trans-[(NH(3))(2)Pt(II)] cross-linking N7 positions could not be confirmed unambiguously, despite the fact that calculations are fully consistent with its existence., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The imidazole ring is part of the lateral chain of histidine. One of the main features of this amino acid is the ability to coordinate copper, especially Cu(2+), because of the intermediate base nature of its imidazole ring, which has a great biological relevance. Proteins such as cytochrome c oxidase, a crucial enzyme in the respiratory chain, and β-amyloid peptide, implicated in the pathology of Alzheimer's disease, are examples of proteins containing histidines in their coordination sphere. Several studies indicate that the presence of this metal ion produces a decrease in the pK(a) of the imidazole ring of histidine. However, there are no reports of systematic studies of pK(a) variation in these types of metal cation complexes. In this work we use density functional theory to study the dependence of imidazole pK(a) with the number of imidazole rings in Cu(2+) coordination environments. The pK(a) of isolated imidazole (ImH), and the pK(a) of imidazole in Cu(2+)(ImH)(m)(H(2)O)(4-m) (m=1-3) complexes have been studied using two different functionals, B3LYP and MPWB1K, which have different percentage of exact exchange, and the highly-correlated CCSD(T) method. Results show that imidazole pK(a) decreases between 2 and 7 units depending on the method employed and the number of imidazole rings coordinating the metal cation. Taking into account that the pK(a) of imidazole is 14, this decrease could be relevant in biological processes., (This journal is © the Owner Societies 2011)

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.

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.

This paper analyses the interaction of Co+ (d8, 1G, and 3F) and Co2+ (d7, 4F) cations with (glycyl)(n)glycine (n = 1-3) oligomers. The structure, relative energies, and binding energies of the complexes formed have been theoretically determined by means of density functional methods. For all Co+ complexes the ground spin state is the triplet one and the most stable structures show tricoordinated geometries. In contrast, for Co2+ systems the lowest energy structures are tricoordinated (n = 1), tetracoordinated (n = 2), and pentacoordinated (n = 3). For both cobalt cations, interaction energies increase with the peptide length. Differences in the coordination properties of the ligands are discussed according to their length as well as to the electronic configuration of the metal cation, and results are compared to those previously obtained for the analogous Cu(+/2+) systems. The IR spectra of the most stable and low energy conformers have been simulated, and a discussion of the main vibrational features is provided.

The C(2v) and C(s) ground and low-lying states of doublet CuO2 are examined for a series of different density functionals (pure, hybrid, and meta-hybrid) and CCSD(T) methods. The effect of changing the B3LYP functional a0 parameter is also explored. CCSD(T) results at the complete basis set limit show that the relative stability of the different electronic states is 2A(2)(C(2v)) < 2A''(Cs) < 2B(2)(C(2v)) < 2A'(C(s)) 2A(1)(C(2v)) < 2B(1)(C(2v)). Unlike CCSD(T), all DFT methods analyzed in this work erroneously predict the end-on 2A'' state as the ground state for CuO2 irrespective of the type of functional and percentage of Hartree-Fock (exact) exchange included in the B3LYP-like functional. Among the different functionals tested, B3LYP gives the best geometries and relative energies for the different electronic states when compared to CCSD(T) results. As for the effect of the a0 parameter, it is found that the B3LYP-like functional yielding better geometries contains 20% of exact exchange, although somewhat unexpectedly, the B3LYP-like functional with a larger contribution of exact exchange (90%) is the one that gives the smaller standard deviation for relative energies.

The structure, relative energies, and binding energies of the complexes formed by the interaction of Cu+ (d10,1S) and Cu2+ (d9,2D) cations with the (glycyl)n glycine (n = 1-3) oligomers have been theoretically determined by means of density functional methods. The most stable structures of the Cu+ systems present linear dicoordination geometries, in agreement with a recent X-ray absorption spectroscopic study of Cu(I) interacting with model dipeptides. This is attributed to an efficient reduction of metal-ligand repulsion through sd sigma hybridization in dicoordinated linear structures. In contrast, for Cu2+ systems the lowest energy structures are tricoordinated (n = 1), tetracoordinated (n = 2), and pentacoordinated (n = 3). For both copper cations, binding energy values show that the interaction energies increase when the peptide chain is elongated. Differences on the coordination properties of the ligands are discussed according to their length as well as to the electronic configuration of the metal cations, which are compared to the Cu+/2+-glycine systems.

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.

The influence of N7 protonation on the mechanism of the N-glycosidic bond hydrolysis in 2'-deoxyguanosine has been studied using density functional theory (DFT) methods. For the neutral system, two different pathways (with retention and inversion of configuration at the C1' anomeric carbon) have been found, both of them consisting of two steps and involving the formation of a dihydrofurane-like intermediate. The Gibbs free energy barrier for the first step is very high in both cases (53 and 46 kcal/mol for the process with inversion and with retention, respectively). However, the N7-protonated system shows a very different mechanism which consists of two steps. The first one leads to the formation of an oxacarbenium ion intermediate, with a Gibbs free energy barrier of 27 kcal/mol, and the second one corresponds to the nucleophilic attack of the water molecule to the oxacarbenium ion and takes place with a barrier of 1.3 kcal/mol. Thus, these results agree with a stepwise SN1 mechanism (DN*AN), with a discrete intermediate formed between the leaving group and the nucleophile approach, and show that N7 protonation strongly catalyzes the hydrolysis of the N-glycosidic bond, making the guanine a better leaving group. Finally, kinetic isotope effects have been calculated for the protonated system, and the results obtained are in very good agreement with experimental data for analogous systems.

The coordination properties of the four natural aromatic amino acids (AA(arom) = Phe, Tyr, Trp, and His) to Cu+ and Cu2+ have been exhaustively studied by means of ab initio calculations. For Cu+-Phe, Cu+-Tyr and Cu+-Trp, the two charge solvated tridentate N/O/ring and bidentate N/ring structures, with the metal cation interacting with the pi system of the ring, were found to be the lowest ones, relative DeltaG(298K) energies being less than 0.5 kcal/mol. The Cu+-His ground-state structure has the metal cation interacting with the NH2 group and the imidazole N. For these low-lying structures vibrational features are also discussed. Unlike Cu+ complexes, the ground-state structure of Cu2+-Phe, Cu2+-Tyr, and Cu2+-Trp does not present cation-pi interactions due to the oxidation of the aromatic ring induced by the metal cation. The ground-state structure of Cu2+-His does not present oxidation of the amino acid, the coordination to Cu2+ being tridentate with the oxygen of the carbonyl group, the nitrogen of the amine, and the N of the imidazole. Other less stable isomers, however, show oxidation of His, particularly of the imidazole ring, which can induce spontaneous proton-transfer reactions from the NH of the imidazole to the NH2 of the backbone. Finally, the computed binding energies for Cu+-AA(arom) and Cu2+-AA(arom) systems have been computed, the order found for the single charged systems being Cu+-His > Cu+-Trp > Cu+-Tyr > Cu+-Phe, in very good agreement with the experimental data.

Cobalt cations are open shell systems with several possible electronic states arising from the different occupations of the 3d and 4s orbitals. The influence of these occupations on the relative stability of the coordination modes of the metal cation to glycine has been studied by means of theoretical methods. The structure and vibrational frequencies have been determined using the B3LYP method. Single-point calculations have also been carried out at the CCSD(T) level. The most stable structure of Co(+)-glycine is bidentate, with the Co(+) cation interacting with the amino group and the carbonyl oxygen of neutral glycine, and the ground electronic state being (3)A. For Co(2+)-glycine, the lowest energy structure corresponds to the interaction of the metal cation with the carboxylate group of the zwitterionic glycine, the ground electronic state being (4)A''.