Carnosine and Carcinine Derivatives Rapidly React with Hypochlorous Acid to Form Chloramines and Dichloramines.

Hypochlorous acid (HOCl) is a highly reactive, toxic species generated by neutrophils via the action of myeloperoxidase in order to destroy invading pathogens. However, when HOCl is produced inappropriately, it can damage host tissue and proteins and plays a role in the initiation and progression of disease. Carnosine, a peptide of β-alanine and histidine, has been shown to react rapidly with HOCl yielding monochloramines and can undergo intramolecular transchlorination.

An ONIOM investigation of the effect of conformation on bond dissociation energies in peptides.

In the present study, we use the ONIOM strategy of Morokuma and coworkers to examine the various CH bond dissociation energies (BDEs) of a small peptide (2ONW) and compare these with values obtained for its component individual amino acid residues. To evaluate suitable methods for ONIOM-based geometry optimizations, we test an "internal consistency" approach against full B3-LYP//B3-LYP results, and find B3-LYP/6-31G(d):AM1 to be appropriate. We find that the BDEs at the α-carbon in 2ONW are generally larger than the corresponding values for the individual residues on their own.

Solvation of the Glycyl Radical.

The effect of adding explicit water molecules to the neutral (N) and zwitterionic (Z) forms of the glycyl radical has been examined. The results show that a minimum of three water molecules is required to stabilize the Z radical as a local minimum, with an energy gap of 123 kJ mol between the N and Z forms at this point, in favor of the N form. Increasing the number of water molecules to ∼20 leads to a converged Z-N energy difference of ∼50 kJ mol still in favor of the N form, even though the radical is not considered fully solvated from a structural point of view.

Computational Tale of Two Enzymes: Glycerol Dehydration With or Without B.

We present a series of QM/MM calculations aimed at understanding the mechanism of the biological dehydration of glycerol. Strikingly and unusually, this process is catalyzed by two different radical enzymes, one of which is a coenzyme-B-dependent enzyme and the other which is a coenzyme-B-independent enzyme. We show that glycerol dehydration in the presence of the coenzyme-B-dependent enzyme proceeds via a 1,2-OH shift, which benefits from a significant catalytic reduction in the barrier.

Effect of Hydrogen Bonding and Partial Deprotonation on the Oxidation of Peptides.

In a recent computational study, we found that hydrogen bonding/partial deprotonation facilitates subsequent electron transfer from amides to HO. We have now analyzed these and related reactions with a glycine derivative as a model peptide, investigating not only reaction energies but also barriers for the individual steps. We find that partial deprotonation not only assists subsequent electron transfer (a sequential proton-loss electron-transfer (SPLET)-type reaction pathway) but also promotes sequential hydrogen-atom transfer (HAT, in a sequential proton-loss hydrogen-atom-transfer (SPLHAT)-type process), both being potential alternatives to direct HAT as routes for peptide oxidation.

Watson-Crick Base Pair Radical Cation as a Model for Oxidative Damage in DNA.

The deleterious cellular effects of ionizing radiation are well-known, but the mechanisms causing DNA damage are poorly understood. The accepted molecular events involve initial oxidation and deprotonation at guanine sites, triggering hydrogen atom abstraction reactions from the sugar moieties, causing DNA strand breaks. Probing the chemistry of the initially formed radical cation has been challenging.

Impact of Hydrogen Bonding on the Susceptibility of Peptides to Oxidation.

The tendency of peptides to be oxidized is intimately connected with their function and even their ability to exist in an oxidative environment. Here we report high-level theoretical studies that show that hydrogen bonding can alter the susceptibility of peptides to oxidation, with complexation to a hydrogen-bond acceptor facilitating oxidation, and vice versa, impacting the feasibility of a diverse range of biological processes. It can even provide an energetically viable mechanistic alternative to direct hydrogen-atom abstraction.

Hydrogen-adduction to open-shell graphene fragments: spectroscopy, thermochemistry and astrochemistry.

We apply a combination of state-of-the-art experimental and quantum-chemical methods to elucidate the electronic and chemical energetics of hydrogen adduction to a model open-shell graphene fragment. The lowest-energy adduct, 1-phenalene, is determined to have a bond dissociation energy of 258.1 kJ mol, while other isomers exhibit reduced or in some cases negative bond dissociation energies, the metastable species being bound by the emergence of a conical intersection along the high-symmetry dissociation coordinate.

Reactivity of disulfide bonds is markedly affected by structure and environment: implications for protein modification and stability.

Disulfide bonds play a key role in stabilizing protein structures, with disruption strongly associated with loss of protein function and activity. Previous data have suggested that disulfides show only modest reactivity with oxidants. In the current study, we report kinetic data indicating that selected disulfides react extremely rapidly, with a variation of 10 in rate constants.

Restricted-Open-Shell G4(MP2)-Type Procedures.

In the present study, we have reformulated the G4(MP2) and G4(MP2)-6X procedures for use with a restricted-open-shell (RO) formalism. We find that the resulting ROG4(MP2) and ROG4(MP2)-6X procedures generally perform comparably to the original unrestricted (U) variants, including their performance on radicals. Our analysis suggests that this is due mainly to the inclusion of empirical parameters that overcome the slightly less good performance of the U variants.

Role of Hydrogen Bonding on the Reactivity of Thiyl Radicals: A Mass Spectrometric and Computational Study Using the Distonic Radical Ion Approach.

Experimental and computational quantum chemistry investigations of the gas-phase ion-molecule reactions between the distonic ions HN(CH)S (n = 2-4) and the reagents dimethyl disulfide, allyl bromide, and allyl iodide demonstrate that intramolecular hydrogen bonding can modulate the reactivity of thiyl radicals. Thus, the 3-ammonium-1-propanethiyl radical (n = 3) exhibits the lowest reactivity of these distonic ions toward all substrates. Theoretical calculations on this distonic ion highlight that its most stable conformation involves a six-membered ring configuration, and that it has the strongest intramolecular hydrogen bond.

Preparation of an ion with the highest calculated proton affinity: -diethynylbenzene dianion.

Owing to the increased proton affinity that results from additional negative charges, multiply-charged anions have been proposed as one route to prepare and access a range of new and powerful "superbases". Paradoxically, while the additional electrons in polyanions increase basicity they serve to diminish the electron binding energy and thus, it had been thought, hinder experimental synthesis. We report the synthesis and isolation of the -diethynylbenzene dianion (-DEB) and present observations of this novel species undergoing gas-phase proton-abstraction reactions.

Frequency Scale Factors for Some Double-Hybrid Density Functional Theory Procedures: Accurate Thermochemical Components for High-Level Composite Protocols.

In the present study, we have obtained geometries and frequency scale factors for a number of double-hybrid density functional theory (DH-DFT) procedures. We have evaluated their performance for obtaining thermochemical quantities [zero-point vibrational energies (ZPVE) and thermal corrections for 298 K enthalpies (ΔH298) and 298 K entropies (S298)] to be used within high-level composite protocols (using the W2X procedure as a probe). We find that, in comparison with the previously prescribed protocol for optimization and frequency calculations (B3-LYP/cc-pVTZ+d), the use of contemporary DH-DFT methods such as DuT-D3 and DSD-type procedures leads to a slight overall improved performance compared with B3-LYP.

α-Hydrogen Abstraction by •OH and •SH Radicals from Amino Acids and Their Peptide Derivatives.

We have used computational quantum chemistry to investigate the thermochemistry of α-hydrogen abstraction from the full set of amino acids normally found in proteins, as well as their peptide forms, by •OH and •SH radicals. These reactions, with their reasonable complexity in the electronic structure (at the α-carbon), are chosen as a consistent set of models for conducting a fairly robust assessment of theoretical procedures. Our benchmarking investigation shows that, in general, the performance for the various classes of theoretical methods improves in the order nonhybrid DFT → hybrid DFT → double-hybrid DFT → composite procedures.

Hydrogen-atom attack on phenol and toluene is ortho-directed.

The reaction of H + phenol and H/D + toluene has been studied in a supersonic expansion after electric discharge. The (1 + 1') resonance-enhanced multiphoton ionization (REMPI) spectra of the reaction products, at m/z = parent + 1, or parent + 2 amu, were measured by scanning the first (resonance) laser. The resulting spectra are highly structured.

Factors influencing the formation of polybromide monoanions in solutions of ionic liquid bromide salts.

Six different bromide salts - tetraethylammonium bromide ([N2,2,2,2]Br, Br), 1-ethyl-1-methylpiperidinium bromide ([C2MPip]Br, Br), 1-ethyl-1-methylpyrrolidinium bromide ([C2MPyrr]Br, Br), 1-ethyl-3-methylimidazolium bromide ([C2MIm]Br, Br), 1-ethylpyridinium bromide ([C2Py]Br, Br), and 1-(2-hydroxyethyl)pyridinium bromide ([C2OHPy]Br, Br) - were studied in regards to their capacity to form polybromide monoanion products on addition of molecular bromine in acetonitrile solutions. Using complementary spectroscopic and computational methods for the examination of tribromide and pentabromide anion formation, key factors influencing polybromide sequestration were identified. Here, we present criteria for the targeted synthesis of highly efficient bromine sequestration agents.

Beyond the Halogen Bond: Examining the Limits of Extended Polybromide Networks through Quantum-Chemical Investigations.

The bonding environments of some polybromide monoanions and networks were examined by quantum-chemical methods to investigate electronic interactions between dibromine-dibromine contacts. Examination of thermodynamic parameters and a bond critical point analysis give strong evidence for such bonding modes, which have been previously treated disparately in the literature. The thermodynamic stability of large polybromides up to [Br37 ](-) was also predicted by these methods.

W2X and W3X-L: Cost-Effective Approximations to W2 and W4 with kJ mol(-1) Accuracy.

We have formulated the W2X and W3X-L protocols as cost-effective alternatives to W2 and W3/W4, respectively, and to supplement our previously developed set of W1X and W3X procedures. The W2X procedure provides an accurate approximation to the all-electron scalar-relativistic CCSD(T)/CBS energy, with a mean absolute deviation (MAD) of 0.6 kJ mol(-1) from benchmark energies provided by the CCSD(T) component in the W4 protocol.

Rapid additive-free selenocystine-selenoester peptide ligation.

We describe an unprecedented reaction between peptide selenoesters and peptide dimers bearing N-terminal selenocystine that proceeds in aqueous buffer to afford native amide bonds without the use of additives. The selenocystine-selenoester ligations are complete in minutes, even at sterically hindered junctions, and can be used in concert with one-pot deselenization chemistry. Various pathways for the transformation are proposed and probed through a combination of experimental and computational studies.

On the inclusion of post-MP2 contributions to double-hybrid density functionals.

In this study, we explore the effect of supplementing the DuT spin-component-scaled double-hybrid density functional method with post-second-order Møller-Plesset-type theory (MP2) correlation terms. We find that the inclusion of additional MP3 correlation energies has almost no effect on the performance. Further addition of correlation effects from MP4 generally leads to a small improvement in the performance.

Gas-phase structure and reactivity of the keto tautomer of the deoxyguanosine radical cation.

Guanine radical cations are formed upon oxidation of DNA. Deoxyguanosine (dG) is used as a model, and the gas-phase infrared (IR) spectroscopic signature and gas-phase unimolecular and bimolecular chemistry of its radical cation, dG˙(+), A, which is formed via direct electrospray ionisation (ESI/MS) of a methanolic solution of Cu(NO3)2 and dG, are examined. Quantum chemistry calculations have been carried out on 28 isomers and comparisons between their calculated IR spectra and the experimentally-measured spectra suggest that A exists as the ground-state keto tautomer.

Outcome-changing effect of polarity reversal in hydrogen-atom-abstraction reactions.

We have examined hydrogen-atom-abstraction reactions for combinations of electrophilic/nucleophilic radicals with electrophilic/nucleophilic substrates. We find that reaction between an electrophilic radical and a nucleophilic substrate is relatively favorable, and vice versa, but the reactions between a radical and a substrate that are both electrophilic or both nucleophilic are relatively unfavorable, consistent with the literature reports of Roberts. As a result, the regioselectivity for the abstraction from a polar substrate can be reversed by reversing the polarity of the attacking radical.

H and D attachment to naphthalene: spectra and thermochemistry of cold gas-phase 1-C10H9 and 1-C10H8D radicals and cations.

Excitation spectra of the 1H-naphthalene (1-C10H9) and 1D-naphthalene (1-C10H8D) radicals, and their cations, are obtained by laser spectroscopy and mass spectrometry of a skimmed free-jet expansion following an electrical discharge. The spectra are assigned on the basis of density functional theory calculations. Isotopic shifts in origin transitions, vibrational frequencies and ionization energies were found to be well reproduced by (time-dependent) density functional theory.

Performance of Density Functional Theory Procedures for the Calculation of Proton-Exchange Barriers: Unusual Behavior of M06-Type Functionals.

We have examined the performance of a variety of density functional theory procedures for the calculation of complexation energies and proton-exchange barriers, with a focus on the Minnesota-class of functionals that are generally highly robust and generally show good accuracy. A curious observation is that M05-type and M06-type methods show an atypical decrease in calculated barriers with increasing proportion of Hartree-Fock exchange. To obtain a clearer picture of the performance of the underlying components of M05-type and M06-type functionals, we have investigated the combination of MPW-type and PBE-type exchange and B95-type and PBE-type correlation procedures.