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Weak nonbonded interaction between a divalent sulfur (S) atom and a main-chain carbonyl oxygen (O) atom are characterized in proteins. However, they have shown distinctly different directional propensities around the O atom from the S...O interactions in small organic compounds, although the linearity of the C-S...O or S-S...O atomic alignment was observed. The results suggested that S...O interactions may control protein structures to some extent and its unique directional properties can be applied to molecular design.

The oxidative regeneration pathways of two three-disulfide mutants of bovine pancreatic ribonuclease A lacking the 65-72 disulfide bond were investigated. Oxidized dithiothreitol was used as an oxidizing agent and 2-aminoethylmethanethiosulfonate as a thiol-blocking agent. Results show that the two mutants, Cys65 and Cys72, folded through the same pathway at a rate lower than that of the wild-type protein. It was also found that the removal of energetic factors causes deceleration of the regeneration of the three-disulfide mutants.

The strength of the nonbonded interaction between an unsymmetric amino nitrogen and the divalent selenium in seven 2-selenobenzylamine derivatives was determined via experimental and theoretical methods. The results, which showed a correlation between the strength of the Se...N interaction and the electrophilic reactivity of the selenium group, indicated the orbital interaction between the antibonding orbital of the Se-X bond and nitrogen lone pair as the cause of the observed phenomenon.

The X-ray structural characterization of an areneselenenyl chloride (ArSeCl), which is strongly stabilized by the intramolecular N...Se-Cl non-bonded interaction has been demonstrated. This interaction is the primary origin of the planar structure of ArSeCl which is also the case for Se-Cl bond. These indicated that the nature of the observed N...Se-Cl interaction is a three-centre-four-electron bond. The features of the electronic structure is discussed.

Mechanistic functions of the amino nitrogens situated at the active center of glutathione peroxidase (GPX), a selenium-containing enzyme, are examined. The model catalyst di-2-(N-cyclohexyl,N-(methylamino)methyl)phenyl diselenide acts exactly as GPX does in the induction catalytic cycle. H NMR spectroscopy revealed the presence of hypervalent Se-N bonding in the catalytic system.

A study is conducted to characterize kinetic and thermodynamic phases in the preconformational folding process of bovine pancreatic ribonuclease A coupled with fast SS formation and SS reshuffling. The transition from kinetic to thermodynamic phase which stabilized SS intermediates is observed to be induced by hydrophobic nucleation as well as generation of the native interactions.

The reliable single amino acid potential (SAAP) functions are obtained for glycine and alanine in water and ether by applying the self-consistent isodensity polarizable continuum model (SPIPCM) method. The results have shown that the intrinsic conformational preferences of the individual amino acids in water are of significant importance not only for describing conformations of a polypeptide chain in the random coil but also for understanding the folding to the secondary and tertiary structures.

The three types of model compounds namely 2-(CH2X)C6H4SeY, 3-(CH2X)-2-C10H6-SeY and 2-XC6H4CH2SeY, to describe the nature of weak nonbonded selenium---halogen interactions, were synthesized and their (super 77) Se NMR spectroscopic behaviors were analyzed in CDCl3. The observations suggested that the nx- sigma Se-Y orbital and electron correlation were dominant factors for the formation of weak Se...X interactions.

Evaluation of weak intramolecular nonbonded Se...F interaction between divalent Se and tertiary amino nitrogen atoms was conducted. A distinct electron-donating character of the lone pairs of organic fluorides was found.

The conformational stability of 2-(methylseleno)ethanol was studied by vibrational spectroscopy and density functional theory. The results showed that intramolecular OH...Se hydrogen bonding was as strong as OH...O and OH...S hydrogen bonding.

A combination of a quench-flow technique and a high-performance liquid chromatography fractionation was used to describe an experimental method to observe unstable reaction disulfide-bonded intermediates. The native-like folded state (N) was first unfolded to reduce the disulfide bond. The resulting unfolded species (U) was unstable relative to N. Further studies showed that the stability of U appeared to be similar to that of the denatured form of N. No evidence for disulfide reshuffling was seen during the reduction time within the detection limit of the mapping method.

Spectroscopic studies reveal the presence of a non-electrostatic C-H bond Se 'hydrogen bond' in diselenocin. Solid-state IR spectral measurements confirms the Se bond H van der Waals contact in the molecule. The conformers of diselenocin show two structural features around the selenium in agreement with covalent directional C-H bond Se interaction. The orbital interaction between the selenium lone pair and the C-H bond is vital to the C-H bond Se insertion.

The conformational unfolding kinetics and the equilibrium stability of the C40A, C95A, C65S and C72S mutants of bovine pancreatic ribonuclease A (RNase A), which are analogue of intermediates des[40-95] and des[65-72, were examined via unfolding experiments. The results suggested that local conformational unfolding limits the rate of the reduction of des[65-72]. Moreover, the reduction of the 40-95 disulfide bond in the native protein and in the des[65-72] intermediate may be rate-limited by the isomerization of Pro93.

To investigate the nature of nonbonded Se…O interactions, three series of 2-substituted benzeneselenenyl derivatives [2-(CHO)C6H4SeX (1), 2-(CH2OH)C6H4SeX, (2), 2-(CH2O/Pr)C6H4SeX (3); X = Cl, Br, CN, SPh, SeAr, Me] were synthesized. The 17O NMR absorption observed for 17O-enriched aldehydes 1 appeared upfield relative to benzaldehyde (PhCHO), while the opposite downfield shifts relative to benzyl alcohol (PhCH2OH) were observed for 17O-enriched alcohols 2 and ethers 3. The magnitude of both the upfield and the downfield shifts became larger as the electron-withdrawing ability of a substituent X increased. Quantum chemical calculations at the B3LYP level revealed that for all model compounds the most stable conformer has an intramolecular nonbonded Se…O interaction. Thus, the relative 17O NMR chemical shifts (ΔΣo) for 1-3 would reflect the strengths of the Se…O interactions. The natural bond orbital (NBO) analysis demonstrated that the stabilization energy due to an no → σ*Se-X orbital interaction (ESe…o) correlates with the Se…O atomic distance on a single curve irrespective of the type of the O atom. On the other hand, the atoms in molecules (AIM) analysis showed that the nonbonded Se…O interactions can be characterized by the presence of a bond critical point, the total energy density (HSe…o) of which decreases with strengthening of the interaction. The results suggested that Se…O interactions have a dominant covalent character rather than an electrostatic one. [ABSTRACT FROM AUTHOR]

Studies the C-H...Se hydrogen bond. Origin of the hydrogen bond; C-H...Se nonbonded interaction in the diselenocin compound; Molecular structure; Solid-state IR spectral measurement; Determination of the spin-spin coupling constant between the selenium and the benzylic hydrogen; Forces involved in the C-H...Se interaction.

Selenosugars are interesting targets of organic synthesis as they would possess potential biological activities. However, 4-selenotherofuranose derivatives, which have trans configuration for the two dihydroxy substituents at the 2,3-positions and a glycoside bond at the anomeric position, are not available in the current selenosugar library. In this study, racemic 4-selenothreofuranose derivatives were synthesized from trans -3,4-dioxygenated tetrahydroselenophenes in 77-99% yields with the α/β selectivity about 7:3 via oxidation and subsequent seleno-Pummerer rearrangement. The acetoxy group introduced at the anomeric position was then substituted with various nucleophiles, including activated 6-chloropurine, which afforded 4'-selenothreonucleoside derivatives, in the presence of BF 3 ·OEt 2 or TMSOTf. The stereochemistry of the selenosugar products was established by 1 H NMR spectroscopy as well as X-ray analysis. The similar α/β selectivity observed in the latter glycosylation reaction to that in the former seleno-Pummerer rearrangement suggested the mediation of a common selenonium intermediate (-Se + =C<). It was also suggested that an unexpected interaction between the ester protecting group at the 3-position of the selenofuranose ring and the anomeric carbon atom decreases the α/β selectivity., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Selenoglutathione (GSeH) is a selenium analogue of naturally abundant glutathione (GSH). In this study, this water-soluble small tripeptide was synthesized in a high yield (up to 98%) as an oxidized diselenide form, i.e., GSeSeG (1), by liquid-phase peptide synthesis (LPPS). Obtained 1 was applied to the investigation of the glutathione peroxidase (GPx)-like catalytic cycle. The important intermediates, i.e., GSe - and GSeSG, besides GSeO 2 H were characterized by 77 Se NMR spectroscopy. Thiol exchange of GSeSG with various thiols, such as cysteine and dithiothreitol, was found to promote the conversion to GSe - significantly. In addition, disproportionation of GSeSR to 1 and RSSR, which would be initiated by heterolytic cleavage of the Se-S bond and catalyzed by the generated selenolate, was observed. On the basis of these redox behaviors, it was proposed that the heterolytic cleavage of the Se-S bond can be facilitated by the interaction between the Se atom and an amino or aromatic group, which is present at the GPx active site. On the other hand, when a catalytic amount of 1 was reacted with scrambled 4S species of RNase A in the presence of NADPH and glutathione reductase, native protein was efficiently regenerated, suggesting a potential use of 1 to repair misfolded proteins through reduction of the non-native SS bonds.

To elucidate the effects of ring structure and a substituent on the glutathione peroxidase- (GPx-) like antioxidant activities of aliphatic selenides, series of water-soluble cyclic selenides with variable ring size and polar functional groups were synthesized, and their antioxidant activities were evaluated by NADPH-coupled assay using H2O2 and glutathione (GSH) in water and also by NMR spectroscopy using H2O2 and dithiothreitol (DTT(red)) in methanol. Strong correlations were found among the GPx-like activity in water, the second-order rate constants for the oxidation of the selenides, and the HOMO energy levels calculated in water. The results support the conclusion that the oxidation process is the rate-determining step of the catalytic cycle. On the other hand, such correlations were not obtained for the activity observed in methanol. The optimal ring size was determined to be five. The type of substituent (NH2 < OH < CO2H) and the number can also control the activity, whereas the stereoconfiguration has only marginal effects on the activity in water. In methanol, however, the activity rank could not be explained by the simple scenarios applicable in water.

Although the catalytic triad of glutathione peroxidase (GPx) has been well recognized, there was little evidence for the relevance of the interactions among the triad amino acid residues, i.e., selenocysteine (U), glutamine (Q), and tryptophan (W), to the GPx antioxidative functions. Using a designed selenopeptide having an amino acid sequence of GQAUAWG, we demonstrate here that U, Q, and W present at the active site can interact with each other to exert the enzymatic activity. The amino acid sequence was chosen on the basis of the Monte Carlo molecular simulation for various selenopeptides in polarizable continuous water using the SAAP force field (SAAP-MC). Measurement of the GPx-like activity for the selenopeptide obtained by solid-phase peptide synthesis revealed that the antioxidant activity is cooperatively enhanced by the presence of Q and W proximate to U, although the activity was low compared to selenocystine (U2). The effect of Q on the activity was more important than that of W. In addition, the fluorescence spectrometry suggested a close contact between U and W. These experimental observations were supported by SAAP-MC simulation as well as by ab initio calculation. The latter further suggested that the interaction mode among the triad changes depending on the intermediate states.

Selenium centered radical cations in aliphatic selenium compounds are stabilized by formation of two-center-three electron (2c-3e) hemi bonds either with nearby heteroatoms forming monomer radicals or with selenium atoms of the parent molecules forming dimer radicals. Such radicals in aromatic selenium compounds would generally be stabilized as monomers by the delocalization of the spin density along the aromatic ring. To test the assumption if aromatic selenides having Se···X nonbonding interactions can show different types of radical cations, we have performed pulse radiolysis studies of three structurally related aromatic selenium compounds and the results have been substantiated with cyclic voltammetry and quantum chemical calculations. The three aromatic selenium compounds have functional groups like -CH2N(CH3)2 (1), -CH2OH (2), and -CH3 (3) at ortho position to the -SeCH3 moiety. The energy of Se···X nonbonding interactions (E(nb)) for these compounds is in the order 1 (Se···N) > 2 (Se···O) > 3 (Se···H). Radical cations, 1(•+), 2(•+) and 3(•+) were produced by the one-electron oxidation of 1, 2 and 3 by radiolytically generated (•)OH and Br2(•-) radicals. Results on transient spectra, lifetime, and secondary reactions of 1(•+), 2(•+), and 3(•+) indicated that 1(•+) shows a significantly different absorption spectrum, longer lifetime, and less oxidizing power compared to those of 2(•+) or 3(•+). Quantum chemical calculations suggested that 1(•+) is stabilized by the formation of a 2c-3e bond between Se and N atoms, whereas 2(•+) and 3(•+) acquire stability through the delocalization of the spin density on the aromatic ring. These results provide evidence for the first time that stronger nonbonding interactions between Se···N in the ground state, facilitate the formation of stabilized radical cations, which can significantly influence the redox chemistry and the biological activity of aromatic selenium compounds.

To investigate the nature of nonbonded Se...O interactions, three series of 2-substituted benzeneselenenyl derivatives [2-(CHO)C6H4SeX (1), 2-(CH2OH)C6H4SeX, (2), 2-(CH2OiPr)C6H4SeX (3); X = Cl, Br, CN, SPh, SeAr, Me] were synthesized. The 17O NMR absorption observed for 17O-enriched aldehydes 1 appeared upfield relative to benzaldehyde (PhCHO), while the opposite downfield shifts relative to benzyl alcohol (PhCH2OH) were observed for 17O-enriched alcohols 2 and ethers 3. The magnitude of both the upfield and the downfield shifts became larger as the electron-withdrawing ability of a substituent X increased. Quantum chemical calculations at the B3LYP level revealed that for all model compounds the most stable conformer has an intramolecular nonbonded Se.O interaction. Thus, the relative 17O NMR chemical shifts (DeltadeltaO) for 1-3 would reflect the strengths of the Se...O interactions. The natural bond orbital (NBO) analysis demonstrated that the stabilization energy due to an nO --> sigma Se-X orbital interaction (ESe...O) correlates with the Se...O atomic distance on a single curve irrespective of the type of the O atom. On the other hand, the atoms in molecules (AIM) analysis showed that the nonbonded Se...O interactions can be characterized by the presence of a bond critical point, the total energy density (HSe...O) of which decreases with strengthening of the interaction. The results suggested that Se...O interactions have a dominant covalent character rather than an electrostatic one.