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The [2+2] cycloreversion of silacyclobutane (SCB) and its two methyl-substituted derivatives, 1-methyl-1-silacyclobutane (MSCB) and 1,1-dimethyl-1-silacyclobutane (DMSCB), were studied using ab initio quantum chemistry calculations. The second-order Moller-Plesset (MP2) perturbation theory, complete active space self-consistent field (CASSCF), and coupled clusters methods were used to explore both the concerted and the stepwise cycloreversions of the three molecules. In addition to the orbital symmetry-forbidden supra-supra [2s+2s] transition state, a new orbital symmetry-allowed supra-antara [2s+2a] transition state was discovered for the concerted route for all three molecules. Both methyl substitution and temperature play a role in the kinetic competition between the [2s+2s] and [2s+2a] routes. At 0 and 298 K, the concerted [2s+2a] cycloreversion is kinetically more favorable than the [2s+2s] cycloreversion for SCB, but the opposite is true for MSCB and DMSCB. With increasing temperatures to above 600 and 1800 K, the [2s+2a] cycloreversion becomes more favorable for MSCB and DMSCB, respectively. The methyl substitutions on Si atoms also affect the stability of the diradical intermediate formed by Si-C bond rupture, leading to a less stable diradical with increasing methyl groups.

By combining MD simulations and AFS experimental technique, we demonstrated a powerful approach for rational design and single molecule testing of novel inhibitor molecules which can block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. We designed and tested novel pseudo-peptide amyloid-β (Aβ) inhibitors that bind to the Aβ peptide and effectively prevent amyloid-amyloid binding. First, molecular dynamics (MD) simulations have provided information on the structures and binding characteristics of the designed pseudo-peptides targeting amyloid fragment Aβ (13-23). The binding affinities between the inhibitor and Aβ as well as the inhibitor to itself have been estimated using Umbrella Sampling calculations. Atomic Force Spectroscopy (AFS) was used to experimentally test several proposed inhibitors in their ability to block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. The experimental AFS data are in a good agreement with theoretical MD calculations and demonstrate that three proposed pseudo-peptides bind to amyloid fragment with different affinities and all effectively prevent Aβ-Aβ binding in similar way. We propose that the designed pseudo-peptides can be used as potential drug candidates to prevent Aβ toxicity in Alzheimer's disease.

Aggregation of amyloid beta peptide (Aβ) and inflammatory processes associated with the generation of superoxide, hydrogen peroxide, and hydroxyl radicals are responsible for neurotoxicity in Alzheimer’s disease. The latter are a result of the redox activity of copper-bound Aβ complexes with molecular oxygen. A ligand (PI1), previously designed to compete with Aβ for copper, and a pseudopeptide (SGC1) with a property of breaking the self-aggregation of Aβ, are attached to each other to form a new pseudopeptide (TGC1) in this study. Using a combination of density functional theory and molecular dynamics simulations, we show that TGC1 should have the ability to inhibit self-aggregation of Aβ, prevent the binding of copper to Aβ, and quench the redox activity of the copper. This trifunctional ligand is a good candidate for development into an anti-Alzheimer drug.

Changes in the stable isotope composition of copper in blood serum as a result of biological processes in the liver were quantified as coupled equilibrium fractionation processes. The model used calculated reduced partition function ratios corresponding to interactions involving individual proteins using Density Functional Theory. This quantified the effect that each process had on the redistribution of copper isotopes in the liver. It was not possible to calculate the reduced partition function of CTR1 as a high resolution crystal structure of its copper binding domains are unavailable at the time of writing, and an optimization process was used to estimate the reduced partition function of CTR1 and constrain the possible isotopic fractionation associated with interactions involving CTR1 independent of direct DFT calculations and assumptions of its structure. The exchange of copper between ceruloplasmin and ATP7B has the most significant impact on the copper isotopic composition of blood serum. The model calculation for the isotopic composition of ceruloplasmin and albumin are δ65Cu = (-0.54 ± 0.10)‰ and δ65Cu = (0.08 ± 0.25)‰ respectively, assuming that serum is 90% ceruloplasmin and 10% albumin using a measured δ65Cu of serum of (0.52 ± 0.08)‰. The model also predicts that the isotopic composition of the tri-nuclear binding motif of ceruloplasmin may be relatively depleted in the lighter isotope of Cu compared to the other copper binding sites by as much as -1.08 ± 0.45‰.

The region encompassing residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization. A number of pseudopeptides have been designed to bind to Aβ(13–23) and been computationally shown to do so with high affinity. More interactions are available in full-length Aβ than are available in the shorter peptide. We describe herein a study by molecular dynamics (MD) of nine distinct complexes formed by one such pseudopeptide, SGA1, with full-length beta amyloid, Aβ(1–42). The relative stabilities of the Aβ–SGA1 complexes were estimated by a combination of MD and ab initio methods. The most stable complex, designated AB1, was found to be one in which SGA1 is bound to the self-recognition site of Aβ(1–42) in an antiparallel β-sheet fashion. Another complex, designated AB3, also involved SGA1 binding to the self-recognition region of Aβ(1–42), albeit with lower affinity. In both AB1 and AB3, SGA1 formed antiparallel β-sheets but to opposite edges of Aβ. A complex, AB4, with similar stability to AB3, was found with a parallel β-sheet in the self-recognition site. A fourth complex, AB7, also with similar stability, formed a parallel β-sheet in the hydrophobic central region of Aβ. In all cases, complexation of SGA1 induced extensive β-sheet structure in Aβ(1–42).

The region encompassing residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of Aβ with many other proteins. We describe herein a study by molecular dynamics of the complexes formed by R (= N-AcAβ(13–23)NH2(N-CH3C(O)HHQKLVFFAEDNH2)) with several pseudopeptides designed to form β-sheets with Aβ(1-40,42) and prevent oligomer and fibril formation. Adhesion to both edges of the R β-strand is examined by structure analysis. Umbrella sampling along a dissociation pathway reveals approximate free energies of binding in the submicromolar range. One of the three pseudopeptides binds strongly to one edge of the R β-strand and another to the opposite edge, while the third displays strong binding to both edges. It is desirable to block both edges of the self-recognition site of Aβ to prevent oligomer formation. The study reveals that this may be accomplished by a single pseudopeptide or two in combination. Thus the pseudopeptides, used singly or in pairs, may be competitive inhibitors of Aβ oligomerization at stoichiometric concentrations.

The region encompassed by residues 13–23 of the amyloid beta peptide (Aβ(13–23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization and also is the site of interaction of Aβ with many other proteins. We describe herein a study by molecular dynamics of N-AcAβ(13–23)NH2 (N-CH3C(O)HHQKLVFFAEDNH2) as a model of full-length Aβ(1–40) or Aβ(1–42) and of its dimers. The effect of pH at or below physiological (pH 7.4) is assessed by protonation of one or more of the His residues. The major conformation of the monomer of the systems is a flexible folded structure. Protonation of one or both His residues does not change the conformation in any significant way. The dimers of protonated and unprotonated systems exist almost exclusively as stable antiparallel β-sheets anchored at both ends by intermolecular salt bridges between Lys16 of one chain and the C-terminal residues Glu22 and Asp23 of the other. We also employ the technique of “umbrella sampling” whereby relative binding affinities of the complexes could be determined. In the case of unsymmetrically protonated species, each complex begins dissociation by releasing the weaker salt bridge, breaking interstrand hydrogen bonds, and losing the β-sheet character. The stronger salt bridge is the last to release and presumably is the first to form in the reverse process of aggregation. Umbrella sampling yields the free energy profiles of the dissociation as a function of the separation of the centres of mass. For each system, the dissociation profile has only a shallow maximum. By implication, the reverse process of assembly has almost no barrier. This is an example of entropy–enthalpy compensation that arises naturally during the molecular dynamics – umbrella sampling simulation.

Neurodegeneration in Alzheimer&rsquo, s disease (AD) is defined by pathology featuring amyloid-&beta, (A&beta, ) deposition in the brain. A&beta, monomers themselves are generally considered to be nontoxic, but misfold into &beta, sheets and aggregate to form neurotoxic oligomers. One suggested strategy to treat AD is to prevent the formation of toxic oligomers. The SG inhibitors are a class of pseudopeptides designed and optimized using molecular dynamics (MD) simulations for affinity to A&beta, and experimentally validated for their ability to inhibit amyloid-amyloid binding using single molecule force spectroscopy (SMFS). In this work, we provide a review of our previous MD and SMFS studies of these inhibitors and present new cell viability studies that demonstrate their neuroprotective effects against A&beta, (1&ndash, 42) oligomers using mouse hippocampal-derived HT22 cells. Two of the tested SG inhibitors, predicted to bind A&beta, in anti-parallel orientation, demonstrated neuroprotection against A&beta, 42). A third inhibitor, predicted to bind parallel to A&beta, was not neuroprotective. Myristoylation of SG inhibitors, intended to enhance delivery across the blood-brain barrier (BBB), resulted in cytotoxicity. This is the first use of HT22 cells for the study of peptide aggregation inhibitors. Overall, this work will inform the future development of peptide aggregation inhibitors against A&beta, toxicity.

β- N-Methylamino-l-alanine (BMAA) is a neurotoxic agent implicated in ALS as well as Parkinson's and Alzheimer's diseases. It is produced by blue-green algae and could find its way via fish and seafood into the human food supply. Isolation from biological samples yields the compound in monomeric and protein-bound form. It has been suggested that the protein-bound fraction may result from genetic misincorporation into proteins in place of serine. Concomitant misfolding of the mutated proteins may be responsible for the neurological diseases. Recent reports that contradict the misincorporation theory leave unresolved the nature of the protein-bound form of BMAA. We have found from quantum mechanical calculations on model systems that it is possible to bind BMAA with high affinity in a noncovalent fashion to proteins. Because of our interest in Alzheimer's disease, molecular dynamics simulations were applied to search for such binding between BMAA and the β-amyloid peptide and to discover whether replacement of either of its two serine residues could affect its aggregation into neurotoxic oligomers. No stable noncovalently bound complex was found, and it was concluded that incorporation of BMAA in place of serine would not alter the conformational dynamics of the β-amyloid peptide.

A component of the neurotoxicity of the beta amyloid peptide (Aβ) of Alzheimer's disease is its ability to generate superoxide, hydrogen peroxide, and hydroxyl radicals by reaction of its reduced copper complex Aβ/Cu+ with molecular oxygen. The objective of the present work was to devise compounds, L, that could remove Cu+ from Aβ/Cu+, with the property that L/Cu+ itself would not be capable of reducing O2 or hydrogen peroxide. We show by density functional calculations that several pincer-type compounds with two imidazole rings and a sulfur or nitrogen have the desired combination of Cu+ binding affinity and Cu2+ reduction potential.

The kinetics and thermochemistry of the decomposition pathways for 1,3-disilacyclobutane (1,3-DSCB) in the gas phase were studied using the second-order Møller-Plesset (MP2) perturbation theory and coupled cluster methods with single, double, and perturbative triple excitations (CCSD(T)). The reactions examined include 2 + 2 cycloreversion to form two silenes by either a concerted or a stepwise mechanism, 1,1-, 1,2-, and 1,3-H(2) elimination, and the ring-opening initiated by 1,2-H shift to form an open-chain 1,3-disilabut-1-ylidene, which undergoes further decomposition to produce two pairs of silene/silylene species. The structures of the transition states for the concerted and the stepwise 2 + 2 cycloreversion pathways are found to resemble closely those reported for the head-to-tail and head-to-head dimerization, respectively. Comparison of the activation barriers demonstrates unambiguously that the stepwise cycloreversion (ΔH(0)(‡) = 66.1 kcal/mol) is favored over the concerted one (ΔH(0)(‡) = 77.3 kcal/mol). A new pathway was established from the 1,4-diradical intermediate in the stepwise cycloreversion to form 1-silylmethylsilene via 1,3-H shift. The concerted 1,1-H(2) elimination is shown to have the lowest activation barrier of all H2 elimination reactions. Overall, the 1,2-H shift in 1,3-DSCB with concerted ring-opening to form 1,3-disilabut-1-ylidene is the most kinetically and thermodynamically favorable decomposition pathway, both at 0 and 298 K.

The structures of complexes between Aβ(1-42) and ferroheme (Fe(II)-heme) were determined by application of Amber and ONIOM(B3LYP/6-31G(d):Amber) methodology. Attachment at each of the three His residues was investigated. In each case, direct bonding of the iron to the His residue is augmented by the formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Aβ (at His13, by Lys16 and the N-terminus; at His14, by both Lys16 and Lys28; at His6, by Arg5) or by H-bonding and hydrophobic interactions (at His6, by Asp7 or Phe20). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest eight structures lying within 36 kJ mol(-1) of each other. The methodology is not precise enough to permit a definitive statement as to the relative stabilities, nor to the absolute binding affinities, which are predicted to be less than 70 kJ mol(-1). The results bear on the question of how heme and copper may bind simultaneously to Aβ. They confirm that the reduced species can bind independently, Cu(+) at His13-His14 and Fe(II)-heme at His6.

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.

Fe(III) porphine complexes and a limited number of Fe(II) porphine complexes were investigated at the 'MP2/LB'//B3LYP/SB level of theory, where SB and LB represent small and large basis sets, 6-31+G(d) and 6-311+G(2df,2p), respectively. Solvation effects were incorporated by the IEFPCM procedure. Most of the ligands whereby the heme prosthetic group is bound in biological systems were modeled in the study. These include H(2)O, Im (imidazole), CH(3)NH(2), CH(3)CO(2)(-), CH(3)S(-), CH(3)PhO(-), OH(-), and Cl(-). Fe(III) porphine, 2(+), and the pentacoordinated complexes, 2(+)(Im), 2(+)(CH(3)NH(2)), and 2(+)(H(2)O), have quartet ground states. The pentacoordinated complexes with negatively charged ligands all have high spin hextet ground states. All of the hexacoordinated complexes have low spin doublet ground states, with the exception of 2(+)(H(2)O)(2) and 2(+)(H(2)O)(Im) which have intermediate spin quartet ground states. None of the pentacoordinated complexes, 2(+)(OH(-)), 2(+)(CH(3)PhO(-)), and 2(+)(CH(3)S(-)), are predicted to form stable hexacoordinated complexes in water with any of the ligands of the present study. The most stable species in water is 2(+)(OH(-)). The hydroxide may be displaced by CH(3)PhOH and CH(3)SH at physiological pH, and by Cl(-), CH(3)CO(2)(-), and Im under acidic conditions, but not by CH(3)NH(3)(+). The relevance of the present results for the pH-dependent transitions of cytochrome c and the fragments, NAcMP8, and NAcMP11, the resting state of cytochrome P450, and the bonding interactions between heme and Aβ, is discussed.

This paper investigates the origin of the anomalous anomeric effect in merosinigrin, a 2-cyanothiane in which the cyano group is axial as expected for the anomeric effect, but in which bond distances are opposite to that expected from the nS→[Formula: see text] orbital interaction, which underlies the classical anomeric effect. The model compounds, 2-cyanooxane, 2-cyanothiane, and 2-cyanoselenane, were synthesized and studied both experimentally and computationally. Both the thia and selena systems displayed an even higher preference for the axial conformation than the oxa system but also exhibited the bond length anomalies found previously in merosinigren. Natural bond order (NBO) analysis of the B3LYP/6–311+G(3df,2p) wave functions of the axial and equatorial forms of the three systems confirmed a weakening of the n→σ* orbital interaction in the O, S, and Se series, and a strengthening of a σ–π*(CN) interaction that explains the bond length reversals observed in the S and Se systems. It also revealed a new mechanism, n→π*, namely, a through-space interaction between the nonbonded lone pair electrons of the heteroatom and the π* orbital of the cyano group, which selects for the axial conformation.

The structures and relative free energies in aqueous solution of the Cu(II) complexes of the “histidine walk” peptides, AcHGGGNH2, AcGHGGNH2, AcGGHGNH2, and AcGGGHNH2, were determined as a function of pH. Numerous structures of each species were found by gaseous- and solution-phase geometry optimization at the B3LYP/6–31G(d) level, and the effect of solvation estimated by the IEFPCM continuum solvation model. Free energies of solvation of the ionic species are large and favour structures with an extended peptide chain. In all Cu(II)–peptide complexes, deprotonation of two amide groups occurs readily at or below pH 7. In each system, the most abundant species at pH 7 is a neutral 1:1 complex with N3O1 coordination pattern. Binding in the forward direction toward the C terminus is preferred. The results are compared to recent experimental spectroscopic and potentiometric studies on related systems. Alternative explanations are offered for some of the experimental observations.

The region encompassing residues 13-23 of the amyloid beta peptide (Aβ(13-23)) of Alzheimer’s disease is the self-recognition site that initiates toxic oligomerization and fibrillization, and also is the site of interaction of Aβ with many other proteins. Peptidic compounds intended to act as β-sheet inhibitors targeted to Aβ(13-23) have been shown to inhibit fibrillization of Aβ and also to reduce its neurotoxicity. We describe herein a study by molecular dynamics (MD) of the complexes between Aβ(13-23) and three (pseudo)peptidic βsheet inhibitors, as well as its homodimer. The monomers of all systems exist predominantly as extended β-strands, with Aβ(13-23) having the greatest flexibility to adopt other conformations. The dimers of all systems exist almost exclusively as stable antiparallel β-sheets anchored at the C-terminus of Aβ(13-23) by salt bridges to the C-terminal residues, Glu22 and Asp23. We also employ an MD technique called “atomic force microscopy” (AFM) to examine the dynamics of dissociation of the complexes in water. Each ligand attached to Aβ(13-23) begins dissociation by peeling back from its C-terminus, breaking interstrand H-bonds, and losing the β-sheet character. The salt bridges are the last to release, and presumably are the first to form in the reverse process of aggregation. The free energy profiles of the dissociation as a function of the separation of the centers-of-mass of all systems show plateau regions in which separation takes place with relatively little or no rise in free energy. For each system the dissociation profile does not have a maximum and reaches a flat plateau. By implication, the reverse process of assembly does not have a barrier. This and the plateau regions in the dissociation profile are examples of entropy-enthalpy compensation that arise naturally during the AFM-MD simulation.

Histidine phosphatases are a class of enzymes that are characterized by the presence of a conserved RHGXRXP motif. This motif contains a catalytic histidine that is being phosphorylated in the course of a dephosphorylation reaction catalyzed by these enzymes. Prostatic acid phosphatase (PAP) is one such enzyme. The dephosphorylation of phosphotyrosine by PAP is a two-step process. The first step involves the transfer of a phosphate group from the substrate to the histidine (His12). The present study reports on the details of the first step of this reaction, which was investigated using a series of quantum chemistry calculations. A number of quantum models were constructed containing various residues that were thought to play a role in the mechanism. In all these models, the transition state displayed an associative character. The transition state is stabilized by three active site arginines (Arg11, Arg15, and Arg79), two of which belong to the aforementioned conserved motif. The work also demonstrated that His12 could act as a nucleophile. The enzyme is further characterized by a His257-Asp258 motif. The role of Asp258 has been elusive. In this work, we propose that Asp258 acts as a proton donor which becomes protonated when the substrate enters the binding pocket. Evidence is also obtained that the transfer of a proton from Asp258 to the leaving group is possibly mediated by a water molecule in the active site. The work also underlines the importance of His257 in lowering the energy barrier for the nucleophilic attack.

Thioredoxin controls the intracellular redox potential through a disulfide/dithiol couple. Under conditions of oxidative stress, this protein functions via one-electron exchange, in which formation of the disulfide radical anion occurs. Combined quantum mechanical (QM) and molecular mechanical (MM) calculations using two- and three-level ONIOM schemes were performed on the thioredoxin (Trx) protein of Chlamydomonas reinhardtii in its oxidized-disulfide and one-electron-reduced forms. In both cases, the active site disulfide moiety was described at the MP2(fc)/6-31+G(d) level, and larger regions of varying sizes around the active site were described at the B3LYP/6-31+G(d) level. The remainder of the 112 residues and 33 water molecules of the crystal structure (PDB entry 1EP7) were described by the AMBER force field. Adiabatic electron affinities were calculated for the disulfide bond in all systems. Separate QM or QM/QM calculations were performed on the QM regions to establish the role of the remainder of the protein on the active site properties. The radical anion species becomes more stable as the number of amide groups in the vicinity increases. One-electron reduction potentials were calculated for the small molecule models, and approximated for the protein for which the values are similar to the experimental one (approximately 0 V). This high reduction potential is due to interaction with the charged end of Lys40, as indicated by mutation in silico to norleucine. The inclusion of the protonated Asp30 side chain and a water molecule in the QM region leads to an increase in the electron affinity. Proton transfer from the Asp30 side chain to the Cys39 sulfur in the radical anion species is strongly disfavored. The radical anion is more stable than the protonated form, which is consistent with experimental results.

Thioredoxin controls the intracellular redox potential through a disulfide/dithiol couple. In conditions of oxidative stress this protein functions by one-electron exchange in which there is formation of the disulfide radical anion. The protonation of this radical is of special importance since it commands the SS bond break leading to the oxidizing thiyl radical. We have studied this reaction by QM/MM procedures. We show that the localization of the proton depends on the protonation state of the residue Asp30. Thus it provides an explanation to the modulation of the redox activity of the protein by the Asp30 residue.

The Abeta1-42 monomer structure was assessed with a 790 ns molecular dynamics (MD) simulation, and the results were compared with the NMR experiment on Abeta10-35 and Abeta1-40. Previous theoretical work in a model of the His13-His14 region of Abeta defined the possible Cu(II) binding geometries at this site (Raffa et al. J. Biol. Inorg. Chem. 2005, 10, 887-902). MD simulations totalling almost 2 micros were also carried out on Cu(II)/Abeta1-42 systems, using the ab initio structures as templates for the copper binding site. This work finds that the copper-free Abeta1-42 system may stabilize after approximately 350 ns into a collapsed coil conformation, and we find good agreement with some, but not all, of the structural features determined experimentally for the Abeta10-35 and Abeta1-40 peptides. The results of the Cu(II)/Abeta1-42 systems are compared to the Cu(II)-free Abeta1-42 simulation.

To model the C-C β-scission reactions of backbone peptide alkoxy radicals, enthalpies and barriers for the fragmentation of four substituted alkoxy radicals have been calculated with a variety of ab initio molecular orbital theory and density functional theory procedures. The high-level methods examined include CBS-QB3, variants of the G3 family, and W1. Simpler methods include HF, MP2, QCISD, B3-LYP, BMK, and MPW1K with a range of basis sets. We find that good accuracy can be achieved with the G3(MP2)//B3-LYP and G3X(MP2)-RAD methods. Lower-cost methods producing reasonable results are single-point energy calculations with UB3-LYP/6-311+G(3df,2p), RB3-LYP/6-311+G(3df,2p), UBMK/6-311+G(3df,2p), and RBMK/6-311+G(3df,2p) on geometries optimized with UB3-LYP/6-31G(d) or UBMK/6-31G(d). Heats of formation at 0 K for the alkoxy radicals and their fragmentation products were also calculated. We predict ΔfH0 values for the alkoxy radicals of -71.4 ((•)OCH2CH [Formula: see text] O), -102.5 ((•)OCH(CH3)CH [Formula: see text] O), -176.6 ((•)OCH(CH3)C(NH2) [Formula: see text] O), and -264.6 ((•)OC(CH3)(NHCH [Formula: see text] O)CH [Formula: see text] O) kJ mol(-)(1). For the fragmentation products NH2C((•)) [Formula: see text] O and CH( [Formula: see text] O)NHC(CH3) [Formula: see text] O, we predict ΔfH0 values of -5.9 kJ mol(-)(1) and -352.8 kJ mol(-)(1).

The possibility of sulfur–nitrogen (S—N) three-electron bond formation in a one-electron oxidized methionine peptide model was investigated computationally following the detection of such species in pulse radiolysis experiments (C. Schöneich, D. Pogocki, G.L. Hug, and K. Bobrowski. J. Am. Chem. Soc. 125, 13700 (2003)). Geometry optimiza tions were carried out at the B3LYP/6-31G(d) level of theory. Relative free energies in aqueous solution at pH 7 were predicted for all intermediates with enthalpy evaluations at the CCSD(T)/6-31+G(d′) level and free energies of solvation predicted using a continuum model (CPCM). Both the initial oxidation product and the intermediate formed at higher pH were identified as cyclic S—N bonded species in which the intramolecular three-electron interaction is between the S atom and the π orbital of the amide group. TD-B3LYP calculations of the UV spectra support the assignments. A mechanism for the conversion to the most stable α-C-centered radical is proposed. The mechanism involves a novel deprotonation–reprotonation via an intermediate backbone-delocalized radical anion.Key words: methionine oxidation, three-electron bonding, S—N bonding, B3LYP.

The origin of the HERON reaction is reviewed from a historical perspective and shown to have its foundation in the unusual properties of bisheteroatom-substituted amides, so-called anomeric amides. The reaction involves migration of anomerically destabilized oxo-substituents on an amide nitrogen to the amide carbon and dissociation of the amide bond. Computational work providing a theoretical basis for the reaction is presented, together with physical organic measurements that support results therefrom. The rearrangement has been observed in a number of chemical transformations of N-alkoxy-N-aminoamides, reactions of 1-acyloxy-1-alkoxydiazenes, N-alkoxy-N-aminocarbamates, N-alkoxyhydroxamic acids, as well as in the gas-phase reactions of N-acyloxy-N-alkoxyamides.Key words: HERON reaction, anomeric amides, rearrangements, hindered esters, concerted reactions.

The structures and energies of three neutrals and four different anions formed by HCl trimers have been examined by theoretical calculations at MP2 and CCSD(T) levels with large basis sets. In order of increasing binding energy for three HCl molecules, the neutrals are: the Y-shaped species, an open chain Z-shaped form and the cyclic C3h form. Dipole bound anion states are possible for both the Z and Y neutrals, but the DBS of the latter is likely to be short lived. The threshold energies for dissociative attachment (DA) of an electron in the reaction: e- + (HCl)3↦ H• + Cl(HCl)2- at the CCSD(T) level are 0.0 and 0.06 eV, respectively for the Y and Z forms. The cyclic species has no dipole moment and does not attach thermal electrons. The structure of the D3h solvated electron (SE) type trimer anion, was also investigated. Although the structure provides for a high electron affinity (0.33 eV relative to the cyclic trimer) it was unstable and rearranged into a ClH.ClH•HCl- (SE(2+1)) species. The latter has an EA of 0.59 eV. Vertical detachment energies were also found for these structures. The EAs and vertical detachment energies of the four HCl anion species are discussed and compared to the corresponding species of HF.

A systematic study of the binding motifs of Cu(II) and Cu(I) to a methionine model peptide, namely, N-formylmethioninamide 1, has been carried out by quantum chemical computations. Geometries of the coordination modes obtained at the B3LYP/6-31G(d) level of theory are discussed in the context of copper coordination by the peptide backbone and the S atom of a methionine residue in peptides with special emphasis on Met35 of the amyloid-beta peptide (Abeta) of Alzheimer's disease. The relative binding free energies in the gas phase, DeltaG(g), are calculated at the B3LYP/6-311+G(2df,2p)//B3LYP/6-31G(d) level of theory, and the solvation affects are included by means of the COSMO model to obtain the relative binding energies in solution, DeltaG(aq). A free energy of binding, DeltaG(aq) = -19.4 kJ mol(-1), relative to aqueous Cu(II) and the free peptide is found for the most stable Cu(II)/Met complex, 12. The most stable Cu(I)/Met complex, 23, is bound by -15.6 kJ mol(-1) relative to the separated species. The reduction potential relative to the standard hydrogen electrode is estimated to be E degrees (12/23) = 0.41 V. On the basis of these results, the participation of Met35 as a low affinity binding site of Cu(II) in Abeta, and its role in the redox chemistry underlying Alzheimer's disease is discussed.

Experimental work has shown that small amounts of HCl strongly enhance electron capture in ice films. The purpose of the present study was to investigate the effect of adsorbed HCl on the interaction of electrons with small clusters of water. Studies were made with clusters of 6 and 12 water molecules with various geometries both with and without one HCl attached. A number of distinct HCl coordination motifs were examined. All of the neutral structures with HCl exhibited zero thresholds for electron attachment and formed dipole bound anionic states (DBS). The relaxation processes for these "initial DBS" depended on the number of H(2)O (n) and on the number and type of H-bonds to the HCl (x). The initial DBS of systems with only O-H...Cl H-binding underwent dissociative electron attachment (DEA), forming H atoms. Relaxation for systems with ClH...OH(2) bonds was more complex. For the two layer n = 12 systems with x = 2 or 3 the HCl proton moved to the nearest oxygen to form H(3)O(+). Then rearrangement of the proton network occurred, and the Cl(-) became solvated by three HO-H...Cl(-) bonds. The presence of Cl(-) and H(3)O(+) increases the dipole moment and the electron binding energy (EBE) of the network. Further stabilization is achieved by decay into deeper DBS electron traps and/or by reaction of the excess electron with H(3)O(+) to form H(*) atoms. The HCl(H(2)O)(6) clusters with a single Cl-H...OH(2) bond behaved differently. They increased their stability by becoming more linear. This raised the dipole moment and the EBE therefore increased, reducing the total energy. None of these species showed any signs of increasing the number of H-bonds to Cl. The implication of these observations for the interpretation of the results of the experiments with 0.2 monolayer of HCl on 5 monolayer of H(2)O at 20 K, and on the possible role of cosmic ray-induced ionization in polar stratospheric clouds in ozone depletion is discussed.

Ab initio calculations were performed on model compounds to examine the possibility of conversion of one-electron-oxidized methionine to homocysteine radical under physiologically relevant conditions. Specifically, we studied competitive proton and methyl cation transfer from the dimethyl sulphide radical cation to three neutral, closed-shell sulphur bases/nucleophiles: H2S, CH3SH and (CH3)2S. The latter two are models for cysteine (or homocysteine) and methionine, respectively. Calculations were performed at the B3LYP/6-31G(d) and levels. The enthalpies of reaction and free energies were determined at 298 K in the gaseous phase and in aqueous solution. CPCM solvation calculations were employed for the solution phase to obtain free energies of solvation. For all three sulphur bases, proton transfer from oxidized (CH3)2S is endothermic and is not hindered by a barrier. Nucleophilic attack by (CH3)2S at the methyl group is strongly exothermic and is impeded by a low enthalpic barrier ( kJ mol−1). The entro...

Potential energy surfaces and threshold energies for dissociative attachment (DA) of an electron to HBr.HX clusters, viz., e - + HBr . HX → H + Br . HX - have been investigated for HX=HBr, HCl, HF and Kr by ab initio calculations at MP2 and CCSD(T) levels with large basis sets. The results show that all three hydrogen halides reduce the threshold energy to zero, while the reduction for the inert gas is much less. These results are in agreement with experimental studies, which show that capture cross sections for thermal energy electrons for the HX=HBr and HCl systems are close to the theoretical maximum. Very substantial reductions in DA threshold can be achieved by clustering, even when only one clustering partner is involved. The extent of reduction appears to depend on the initial starting geometry in the neutral dimer and other factors, as well as the magnitude of the Br−..HX binding energy.

Alzheimer's disease [AD] is the most common cause of dementia among people age 65 and older. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer's disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from Alzheimer's disease. An overview of the currently popular 'amyloid' and 'vascular' hypotheses for AD demonstrates that neither hypothesis by itself can explain all the known histopathological and biochemical lesions seen in Alzheimer's disease. The paper presents a hypothesis that tries to explain the mechanism behind almost all the histopathological changes, and varying clinical manifestations seen in both diagnosed AD and Vascular Dementia [VaD]. The new hypothesis is based on the known dual toxicity of beta amyloid to both vascular and neuronal tissues, their synergy and the resultant net effect on the onset and progression of AD. The new hypothesis therefore will be known as the Amyloid Beta Synergistic Endothelial and Neuronal Toxicity [ABSENT] hypothesis. The ABSENT hypothesis will try to show the common chemical mechanism behind almost all of the pathological changes seen in AD. According to the ABSENT hypothesis, beta amyloid itself generates all the free radicals that cause both vascular dysfunction and the neuronal damage seen in AD. The chemical mechanism proposed is based on evidence from physical chemistry experiments, calculations as well as in vitro/in vivo experiments. The ABSENT hypothesis does not favor one mode of beta amyloid-induced brain damage over the other, rather it considers the net effects of the neuronal stress/damage caused by both the cerebrovascular dysfunction and direct neurotoxicity caused by beta amyloid. The hypothesis states that each patient has a different balance of predisposing factors that modulate the extent of neurotoxicity and cerebrovascular dysfunction caused by beta amyloid and thereby explains the wide range and mixed nature of damage and dysfunction seen in the studies done on patients diagnosed with AD, VaD or 'mixed dementias'. According to the hypothesis, beta amyloid peptides are necessary if not sufficient to cause AD, VaD and mixed senile dementias. The hypothesis, therefore, proposes the term Beta Amyloid Dementias [BAD] to describe the conditions currently covered by the diagnoses of 'AD', 'VaD' and 'Mixed [senile] Dementias'. Finally, the ABSENT hypothesis tries to put forth a direct chemical mechanism behind the apparent synergy and increased association between old age, pre- and coexisting vascular disease, diabetes and AD.

The complexes between the radical cation of dimethyl sulfide 2 and models for eight biologically available electron pair donors, :X (:X = H2O (2a), H2CO (2b), HC(O)NH2 (2c), HC(O)NHCH3 (2d), HCO2- (2e), HCO3- (2f), H2PO4- (2g), and CH3NH2 (2h)), were optimized at the B3LYP/6-31G(d) level of theory. S∴X bond dissociation enthalpies (BDEs) were determined by single point calculations at the CBS−RAD level, a method designed for quantitative thermochemistry of free radicals. The effect of solvation was determined by application of a polarizable continuum model. Only the amine complex is predicted to be stable in water. H2O and H2PO4- make transient complexes, and the remaining complexes are predicted to dissociate spontaneously. The dissociation is driven by entropy and conformationally constrained complexes are predicted to be stable in water. Reduction potentials, E°, accurate to ±0.1 V were calculated for the complexes with dimethyl sulfide and for the amino acid, methionine, both as an isolated amino acid...

Ab initio calculations at the B3LYP/6-31G(d) and CBS-RAD level were carried out to investigate the reaction of α C-centered peroxy radicals of neutral, non-zwitterionic glycine and alanine (AH), and as residues in model peptides, N-formylglycinamide and N-formylalaninamide (PH). Bond dissociation enthalpies (BDEs) were calculated for the α C-O (D α CO), O-O (D O O ) and O-H (D O B ) bonds of glycine and alanine peroxy radicals (AOO, POO) and hydroperoxides (AOOH, POOH). The predicted BDEs at 298 K, in kJ mol - 1 are AOO(Gly), D α CO = 70; AOO(Ala), D α CO=69; POO(Gly), D α CO=89; POO(Ala), D α CO=86; AOOH(Gly), D α CO=237, D O O =203, D O H =371; AOOH(Ala), D α CO = 234, D O O =195, D O H =368; POOH(Gly), D α OH = 266, D O O =207, D O H =380; POOH(Ala), D α CO = 264, D O O = 208, D O H = 383. Values of BDE of the peptides in β-sheet peptide conformations were also estimated by constraining the Ramachandran dihedral angles, Φ and Ψ to, values of -150° and +150°: (S)-POO(Gly), D α CO = 99; (R)-POO(Gly), D α CO = 78; (S)-POO(Ala), D α CO = 88; (R)-POO(Ala), D α CO = 83; (S)-POOH(Gly), D α CO =258, D O O =195, D O H =362; (R)-POOH(Gly), D α CO =278, D O O =217, D O H =404; (S)-POOH(Ala), D α CO = 240, D O O = 192, D O H = 355; (R)-POOH(Ala), D α CO = 270, D O O = 204, D O H = 390. The reactions of "C-peroxy radicals, POO, and "C-alkoxy radicals, PO, were studied in detail.

A one-electron oxidation of a methionine residue is thought to be a key step in the neurotoxicity of the beta amyloid peptide of Alzheimer's disease. The chemistry of the radical cation of N-formylmethioninamide (11•+) and two model systems, dimethyl sulfide (1•+) and ethyl methyl sulfide (6•+), in the presence of oxygen have been studied by B3LYP/6-31G(d) and CBS-RAD calculations. The stable form of 11•+ has a three-electron bond between the sulfur radical cation and the carbonyl oxygen atom of the i − 1 residue. The radical cation may lose a proton from the methyl or methylene groups flanking the oxidized sulfur. Both 11•+ and the resultant C-centered radicals may add oxygen to form peroxy radicals. The calculations indicate that unlike C-centered radicals the sulfur radical cation does not form a covalent bond to oxygen but rather forms a loose ion-induced dipole complex with an S−O separation of about 2.7 A, and is bound by about 13 kJ mol-1 (on the basis of 1•+ + O2). Direct intramolecular abstractio...

Ab initio calculations at the B3LYP/6-31G(d) level and scaled particle theory, combined with entropies of activation derived from experimental Arrhenius A factors, were applied to examine the origin of the loss of gaseous-phase entropy of a substance upon solution. Eight reactions in water were analyzed: H atom reacting with methanol, ethanol, 2-propanol, methanediol and ethylene glycol; and methanethiol reacting with the radicals, methyl, hydroxymethyl, and 2-hydroxy-2-propyl. The results suggest that the observed entropy loss is entirely due to changes in the solvent. The dominant factor is a loss of entropy due to cavity formation. This is partially offset by a corresponding increase in the disorder of the H-bonding network in the case of the larger species.

The structures and reactivities of the alkoxy radicals methoxy (CH3O·), ethoxy (CH3CH2O·), 1-propoxy (CH3CH2CH2O·), 2-propoxy ((CH3)2CHO·), 2-butoxy (CH3CH2CH(CH3)O·), tert-butoxy ((CH3)3CO·), prop-2-enoxy (CH2=CHCH2O·), and but-3-en-2-oxy (CH2=CHCH(CH3)O·) have been investigated at the B3-LYP/6-31G(d) and CBS-RAD levels of theory. Enthalpies of formation (ΔfH°298) were calculated with CBS-RAD for all the alkoxy radicals, the carbonyl and radical products of β-scission reactions, and the transition structures leading to them. The mean absolute deviation between the predicted and available experimental ΔfH°298 values is 5.4 kJ mol–1. Eyring (ΔH‡0, ΔH‡298, ΔG‡298) and Arrhenius (log A, Ea) activation parameters for both the forward (β-scission) and reverse (radical addition to carbonyl) pathways were calculated. Agreement with available experimental data is very good, generally within 1–5 kJ mol–1 for Ea, and 0.5 for log A. The transition structures are found to be substantially polarized, with the departing radical slightly positive, the O atom negative, and the rest of the molecule positive. The barriers for the β-scission reactions decrease with decreasing endothermicity and with decreasing ionization energy of the departing radical.Key words: alkoxy, alkoxyl, radical, addition, carbonyl, β-scission, calculaton, electronic structure, B3LYP, CBS-RAD, thermochemistry.

The binding of Cu(II) to the prion protein is investigated by computations at the B3LYP level of theory on models of the octarepeat domain of the prion protein. The models incorporate the functionality of the glycine (G) and histidine (H) residues which occur in the octarepeat domain, PHGGGWGQ. The copper complexes are designated Cu[HG] and Cu[HGGG]. Coordination to the metal via the imidazole ring of the histidine, the amide carbonyl groups, and the backbone nitrogen atom of the amide groups were examined, as well as several protonation/deprotonation states of each structure. EPR and CD titration experiments suggest that the octarepeat segments of the unstructured N-terminal domain of prion protein can bind Cu(II) in a 1:1 Cu-to-octarepeat ratio. The results identify the extent to which the Cu(II) facilitates peptide backbone deprotonation, and the propensity of binding in the forward (toward the C-terminus) direction from the anchoring histidine residue. A plausible mechanism is suggested for changing from amide O-atom to deprotonated amide N-atom coordination, and for assembly of the observed species in solutions of Cu[PrP] and truncated models of it. A structure is proposed which has the N2O2 coordination pattern for the minor component observed experimentally by EPR spectroscopy for the Cu[HGGG] model. The most stable neutral Cu[HGGG] structure found, with coordination environment N3O1, corresponds to that observed for Cu[HGGGW] and Cu[HGGG] both in the solid state and as the major component in solution at neutral pH. Electronic supplementary material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00775-002-0386-7.

Using the pulse radiolysis and other radiation chemical techniques, the reaction kinetics of ˙CH3 and ˙CH2OH radicals with alanine anhydride, glycine anhydride and sarcosine anhydride were examined in aqueous solution. The second order rate constant of reaction of ˙CH3 with alanine anhydride has been determined at 2 × 105 dm3 mol−1 s−1. A very similar value (8 × 104 dm3 mol−1 s−1) has been obtained by measuring the methane and ethane yields as a function of the alanine anhydride concentration at different dose rates and evaluation of these data by computer analysis. Similar experiments carried out with glycine anhydride and sarcosine anhydride yielded identical rate constants of 4 × 104 dm3 mol−1 s−1 for these compounds. It was found that ˙CH2OH radical does not react with alanine anhydride at an appreciable rate (k

Dissociative attachment (DA) of an electron to the dimers of HF and HCl, reaction (1) (1) has been investigated by theoretical calculations at MP2 and CCSD(T) levels with large basis sets. Transition structures (TSs) for the loss of an H atom and formation of the FHF− and ClHCl− anions were located by analytic methods. Initial electron attachment to HF.HF dimer occurs without activation and yields a dipole-bound anion state (DBS) as shown previously. Reaction (1) is endothermic by 65.8 kJ/mol at the CCSD(T)/aug-cc-pVDZ level. An intermediate ion-induced dipole complex between H · and FHF− is reached from the DBS over a potential barrier of 66.6 kJ/mol. Analysis of the charge distribution as a function of the distance to the departing H · reveals that the diffuse DBS collapses to a much more compact valence configuration prior to the TS being reached. In the valence configuration, the electron occupies the σ* orbital of the terminal HF bond. DA to HCl.HCl differs from the fluorine case in several important respects. HCl.HCl does not form a DBS. Rather, electron attachment occurs by direct insertion into the σ* orbital of the terminal HCl bond with an activation energy of 20.3 kJ/mol. As in the fluorine case, electron capture occurs before the TS. The electron density collapses to a valence configuration when the HCl bond is stretched to about 1.45 A, intermediate between that in the neutral dimer, 1.28 A, and in the TS to DA, 1.57 A. A “T-shaped” ion-induced dipole complex, bound by about 2 kJ/mol, lies between the TS and the separated H atom and ClHCl− anion products. With respect to DA, the chlorine system is intermediate between the fluorine system and the previously reported bromine system. The latter was found to undergo DA with a 0.0-kJ/mol barrier. © 2003 Wiley Periodicals, Inc. Int J Quantum Chem, 2003

The reactions of methanethiyl radicals (CH3S˙) with the cyclic anhydrides of glycine (1a), alanine (L,L-1b and D,L-1b), and sarcosine (1c), and the acyclic peptides, N-formylglycinamide (3a) and N-formylalaninamide (3b), were studied by means of theoretical calculations at the B3LYP/6-311+G(d,p) level of theory. Free energies in the gas phase were determined in the classical harmonic oscillator-rigid rotator model, and used to estimate rates of H-transfer reactions at the αC-site of the peptides. The effects of aqueous solution were estimated by the SCIPCM procedure in combination with modified experimental Arrhenius A-factors to calculate solution phase rate constants. The reactions are discussed in terms of the charge and spin polarisation in the transition state, as determined by AIM analysis. Rate constants calculated by this semiempirical Arrhenius approach are in very good agreement with available experimental data on the reaction of D3N+CH2CH2S˙ with 1a and 1c but not 1b in D2O. The rate constants for the reaction of CH3S˙ with 3a and 3b are also in very good agreement with experimental data on the N-acetyl analogues. Contrary to experiment, the cyclic alanine anhydrides, L,L-1b and D,L-1b, were predicted to react more than an order of magnitude more quickly than any of the other dipeptides.

The Radical Model of Alzheimer's Disease (AD) is presented in some detail. The model provides a unified picture for the role of the amyloid beta peptide (Abeta), Met35, copper ions, oxygen, beta sheet secondary structure, and the generation of hydrogen peroxide, in mediating oxidative stress in AD. It predicts a role for glycyl radicals as long-lived species which can transport the damage into cell membranes and initiate lipid peroxidation. Previous work has established the thermodynamic and kinetic viability of most of the steps. In the present work, QM/MM and Amber calculations reveal that self assembly of antiparallel beta-sheet which brings Met35 into the required close proximity to a glycine residue is more likely if the residue is Gly29 or Gly33, than any of the other four glycine residues of Abeta.

Treatment of N-alkoxy-N-chloro- or N-acetoxyamides with sodium azide in aqueous acetonitrile results in SN2 displacement of chlorine or acetate and the formation of reactive N-alkoxy-N-azidoamides which undergo a concerted decomposition to esters and nitrogen. The properties of the model N-azido-N-methoxyformamide have been computed at the B3LYP/6-31G* hybrid density functional level of theory. It is a typical anomeric amide in that the nitrogen is strongly sp3 hybridised resulting in a low amide isomerisation barrier. It decomposes in a two-step process involving exothermic loss of N2 to give 1-formyl-1-methoxydiazene which spontaneously undergoes a HERON decomposition to methyl formate and N2. Overall, the process is highly exothermic (ΔG between −654 and −659 kJ mol−1). The competitive one-step HERON process involving formation of methyl formate and tetrazene is kinetically unfavourable. Sterically hindered ester formation will be facilitated by both exothermicity and a transition state for ester formation which avoids a sterically crowded tetrahedral intermediate.

The Arrhenius parameters and rates of reaction of three hydroxyradicals, methyl radical, and the hindered primary C-centred radical from t-butyl alcohol with dithiothreitol were measured by pulse radiolysis in water. The bimolecular rate constants were found to be in the order: ˙C(CH3)2OH > ˙CH(CH3)OH > ˙CH2OH > ˙CH3 > ˙CH2C(CH3)2OH. The reaction of three of these, ˙C(CH3)2OH, ˙CH2OH, and ˙CH3, with methanethiol were examined at the ab initio B3LYP/6311+G(d,p) level, coupled with transition state theory, both in the gas phase and in solution. The solvent effects are evaluated by two different continuum models (SCIPCM, CPCM), coupled with a novel approach to the calculation of the solution phase entropy. The reaction is discussed in terms of the charge and spin polarization in the transition state, as determined by AIM analysis, and in terms of orbital interaction theory. Rate constants, calculated by transition state theory are in good agreement with the experimental data.

This paper examines the stabilities of singly charged anions with the linear opposed dipole structures: FH−HF, ClH−HCl and BrH−HBr at MP2 and CCSD(T) levels. With 6-311+G(3df,2p) basis sets on Cl and Br and aug-cc-pvdz on H and F, MP2 structures were obtained for all three systems. Since the neutral dimers with opposed dipoles are unstable, the energies for the electron detachment processes were evaluated relative to separated free neutrals, viz.: XH−HX·- → e- + 2HX. At the CCSD(T) level these energies were 0.26 and 0.84 V for HCl and HBr, respectively, but the value for HF is negative. The addition of diffuse orbitals at the central point between the two H atoms lowered the energy and caused the H−H distance in the FH−HF species to increase. Also the excess electron moved into the diffuse orbitals and the species assumed a solvated electron structure, a finding which is in agreement with previous work. In contrast, for the HCl and HBr species the addition of diffuse orbitals had no significant effect. ...

The 1-methyl-1-cyclohexyl cation 1 has previously been proposed to exist in superacid solution as a rapidly equilibrating pair of structures, one isomer involving C–C hyperconjugation, and a counterpart with axial C–H hyperconjugation (hyperconjomers). Using a combination of three techniques, which successfully compare theoretical results with experimental data, we have now obtained virtual proof for this concept. These three calculational procedures involve matching the experimental energy difference for the C–C and C–H hyperconjomers of 1, together with the cis-3,5-dimethyl 2 and 4,4-dimethyl 3 analogs of 1, to an accuracy of ±2 kJ mol−1 (solvation-simulation studies), a successful simulation of the α-d4 equilibrium isotope effects for the 1, 2 and 3 cation systems, and, finally, a close simulation of the average 13C NMR spectra for mixtures of these C–C and C–H hyperconjomers in the 1, 2 and 3 systems. These results have interesting implications for solvolysis studies of tertiary cyclohexyl systems, a full discussion of which is presented.

Methionine in glycine-rich regions of both β-amyloid peptide and prion peptide is thought to be crucial to their neurotoxic properties. We postulate here a role for methionine in the propagation of oxidative damage. The S−H bond dissociation enthalpies, BDE(S−H)s, of dimethylsulfonium ion (CH3)2SH+ and a S-protonated methionine residue of a polypeptide strand are estimated to be 351 and 326−331 kJ mol-1, respectively, by the application of calculations at the B3LYP level with large basis sets. These species are direct products of H atom abstraction by radical cations of sulfides. The reactions between a glycine residue and the radical cations of (CH3)2S and Met were investigated and the transition structures for H atom transfer located. The results suggest that it is thermodynamically feasible for the S-ionized form of Met to cause oxidative damage at the αC−H site of almost any amino acid residue of a nearby polypeptide strand (BDE(αC−H) = 330−360 kJ mol-1) or to nearby lipids with a bis(allylic) methyle...

Experimental studies have shown that the dissociative attachment of electrons to HBr monomer; viz., HBr + e- → H• + Br- is an endothermic process, which requires electrons of energy near the endothermicity (ΔE = +38 kJ/mol). In contrast the attachment to the dimer via the reaction: HBr·HBr + e- ⇌ HBr·HBr•- → H• + BrHBr- proceeds readily with electrons of thermal (i.e., near zero) energy. The energetics of the reactions with both the monomer and the dimer have been studied by ab initio methods. In each case the structure of the neutral and anion species have been computed using large basis sets and diffuse orbitals at the MP2 level. Energies have been obtained at this level and at the CCSD(T) level. The initial interaction of the free electron with the molecule produces a dipole continuum state (DCS) of the anion. The DCS subsequently undergoes a transition to a bound state via an avoided crossing. On the basis of the CCSD(T) energies, the H−Br•-···HBr interaction lowers the energy for dissociation of the...

Ab initio calculations at the B3LYP/6-31G(d) level of theory were carried out on selected cyclic hydrogen-bonded (H-bonded) dimers of glycine and alanine as models for β-sheets and on the αC-centered radicals derived from them. The structures mirrored the cycles found in the H-bonded network of parallel and antiparallel β-sheet secondary structure, and were otimized both with and without enforcement of constraints on the Φ,Ψ torsion angles. Transition structures for the migration of an H atom from an αC site to another αC site or to an S atom were located. It was found that the presence of a H-bonded strand of a β-sheet has little effect on the αC−H bond dissociation enthalpy (BDE) of glycine but raises the BDE of other residues by a significant amount. The parallel β-sheet structure and Φ,Ψ angles lead to a significant increase in BDE, relative to the random coil structure, due to loss of captodative stabilization. The antiparallel β-sheet structure and Φ,Ψ angles do not lead to a significant increase in...