Energetically favorable cation−π interactions play important roles in numerous molecular recognition processes in chemistry and biology. Herein, we present synergistic experimental and computational physical–organic chemistry studies on 2,6-diarylanilines that contain flanking meta/para-substituted aromatic rings adjacent to the central anilinium ion. A combination of measurements of pKa values, structural analyses of 2,6-diarylanilinium cations, and quantum chemical analyses based on the quantitative molecular orbital theory and a canonical energy decomposition analysis (EDA) scheme reveal that through-space cation−π interactions essentially contribute to observed trends in proton affinities and pKa values of 2,6-diarylanilines.

Trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nε-trimethyllysine in the first step of carnitine biosynthesis in humans. Studies on TMLH have been hampered by the lack of established chemical methods. We report that an Nε-trimethyllysine analogue that contains the fluoromethyl group can be used as a 1H and 19F NMR probe for studies on TMLH catalysis.

Histone lysine methylation is regulated by Nε-methyltransferases, demethylases, and Nε-methyl lysine binding proteins. Thermodynamic, catalytic and computational studies were carried out to investigate the interaction of three epigenetic protein classes with synthetic histone substrates containing L- and D-lysine residues. The results reveal that out of the three classes, Nε-methyl lysine binding proteins are superior in accepting lysines with the D-configuration.

Trimethyllysine hydroxylase (TMLH) is an Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase involved in the biomedically important carnitine biosynthesis pathway. A combination of synthetic and NMR studies provides direct evidence that human TMLH catalyzes the stereoselective conversion of (2S)-Nε-trimethyllysine to (2S,3S)-3-hydroxy-Nε-trimethyllysine.

Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields.

Supramolecular protein assemblies are an emerging area within the chemical sciences, which combine the topological structures of the field of supramolecular chemistry and the state-of-the-art chemical biology approaches to unravel the formation and function of protein assemblies. Recent chemical and biological studies on natural multimeric protein structures, including fibers, rings, tubes, catenanes, knots, and cages, have shown that the quaternary structures of proteins are a prerequisite for their highly specific biological functions. In this review, we illustrate that a striking structural diversity of protein assemblies is present in nature. Furthermore, we describe structure–function relationship studies for selected classes of protein architectures, and we highlight the techniques that enable the characterisation of supramolecular protein structures.

Unactivated carboxylic esters and primary amines undergo calcium-catalysed direct amide bond formation in excellent yields under homogeneous conditions in toluene. This green and mild reaction proceeds chemoselectively with esters, whereas related carboxylic acids and amides remain unreactive.

Development of catalytic amide bond formation reactions from readily available starting materials remains a challenging task for modern organic chemistry. Herein, we report that unactivated carboxylic esters and amines react in the presence of 10 mol % of zirconocene dichloride (Cp2ZrCl2) in toluene at 110 °C to afford amides in very good to excellent conversions. The Zr-catalyzed reaction is amenable for the amidation of aliphatic and aromatic carboxylic esters with primary and secondary amines. The reaction proceeds with almost complete retention of configuration for chiral esters and chiral amines.

Catenane structures, in which two or more rings are mechanically interlocked, have historically occupied one of the central places in the field of supramolecular chemistry. In contrast to synthetic small-molecule catenanes, examples of naturally-occurring catenanes are scarce. Here, we report thermodynamic and enzymatic studies on CS2 hydrolase, which exists in solution as a mixture of unique hexadecameric catenane and octameric ring forms. A combination of field-flow fractionation coupled to multi-angle laser light scattering (FFF-MALLS) and native mass spectrometric analyses revealed that the catenane form is converted into the ring form at elevated temperatures, whereas the ring does not assemble into the catenane under the same conditions. Measurements of the enzyme kinetics for the conversion of CS2 into COS and H2S showed that the ring form of CS2 hydrolase possesses higher enzyme efficiency (per monomer) than the catenane form, whereas the catenane form is overall more active (per assembly).

Transmission electron microscopic studies on CS2 hydrolase provide direct evidence for the existence of the hexadecameric catenane and octameric ring topologies. Reconstructions of both protein assemblies are in good agreement with crystallographic analyses of the catenane and ring forms of CS2 hydrolase.

Unactivated carboxylic acids and amines undergo organocatalytic Ph3P/CCl4-mediated amide bond formation by employing in situ reduction of triphenylphosphine oxide to triphenylphosphine in the presence of diethoxymethylsilane and bis(4-nitrophenyl)phosphate.

CS2 hydrolase, a zinc-dependent enzyme that converts carbon disulfide to carbon dioxide and hydrogen sulfide, exists as a mixture of octameric ring and hexadecameric catenane forms in solution. A combination of size exclusion chromatography, multi-angle laser light scattering, and mass spectrometric analyses revealed that the unusual catenane structure is not an artefact, but a naturally occurring structure.

Benzothiazole-2-sulfonamides react with an excess of hydroxylamine in aqueous solutions to form 2-hydroxybenzothiazole, sulfur dioxide, and the corresponding amine. Mechanistic studies that employ a combination of structure–reactivity relationships, oxygen labeling experiments, and (in)direct detection of intermediates and products reveal that the reaction proceeds via oxygen attack, and that oxygen incorporated in the 2-hydroxybenzothiazole product derives from hydroxylamine. The reaction, which is performed under mild conditions, can be used as a deprotection method for cleavage of benzothiazole-2-sulfonyl-protected amino acids.

Supramolecular protein assemblies are an emerging area within the chemical sciences, which combine the topological structures of the field of supramolecular chemistry and the state-of-the-art chemical biology approaches to unravel the formation and function of protein assemblies. Recent chemical and biological studies on natural multimeric protein structures, including fibers, rings, tubes, catenanes, knots, and cages, have shown that the quaternary structures of proteins are a prerequisite for their highly specific biological functions. In this review, we illustrate that a striking structural diversity of protein assemblies is present in nature. Furthermore, we describe structure–function relationship studies for selected classes of protein architectures, and we highlight the techniques that enable the characterisation of supramolecular protein structures.

Catenane structures, in which two or more rings are mechanically interlocked, have historically occupied one of the central places in the field of supramolecular chemistry. In contrast to synthetic small-molecule catenanes, examples of naturally-occurring catenanes are scarce. Here, we report thermodynamic and enzymatic studies on CS2 hydrolase, which exists in solution as a mixture of unique hexadecameric catenane and octameric ring forms. A combination of field-flow fractionation coupled to multi-angle laser light scattering (FFF-MALLS) and native mass spectrometric analyses revealed that the catenane form is converted into the ring form at elevated temperatures, whereas the ring does not assemble into the catenane under the same conditions. Measurements of the enzyme kinetics for the conversion of CS2 into COS and H2S showed that the ring form of CS2 hydrolase possesses higher enzyme efficiency (per monomer) than the catenane form, whereas the catenane form is overall more active (per assembly).

CS2 hydrolase, a zinc-dependent enzyme that converts carbon disulfide to carbon dioxide and hydrogen sulfide, exists as a mixture of octameric ring and hexadecameric catenane forms in solution. A combination of size exclusion chromatography, multi-angle laser light scattering, and mass spectrometric analyses revealed that the unusual catenane structure is not an artefact, but a naturally occurring structure.

Trimethyllysine hydroxylase (TMLH) is a non-haem Fe(II) and 2-oxoglutarate dependent oxygenase that catalyses the C-3 hydroxylation of an unactivated C–H bond in L-trimethyllysine in the first step of carnitine biosynthesis. The examination of trimethyllysine analogues as substrates for human TMLH reveals that the enzyme does hydroxylate substrates other than natural L-trimethyllysine.

Trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nε-trimethyllysine in the first step of carnitine biosynthesis in humans. Studies on TMLH have been hampered by the lack of established chemical methods. We report that an Nε-trimethyllysine analogue that contains the fluoromethyl group can be used as a 1H and 19F NMR probe for studies on TMLH catalysis.

Development of catalytic amide bond formation reactions has been the subject of the intensive investigations in the past decade. Herein we report an efficient organophosphorus-catalysed amidation reaction between unactivated carboxylic acids and amines. Poly(methylhydrosiloxane), a waste product of the silicon industry, is used as an inexpensive and green reducing agent for in situ reduction of phosphine oxide to phosphine. The reported method enables the synthesis of a wide range of secondary and tertiary amides in very good to excellent yields.

Unactivated carboxylic acids and amines undergo organocatalytic Ph3P/CCl4-mediated amide bond formation by employing in situ reduction of triphenylphosphine oxide to triphenylphosphine in the presence of diethoxymethylsilane and bis(4-nitrophenyl)phosphate.

Transmission electron microscopic studies on CS2 hydrolase provide direct evidence for the existence of the hexadecameric catenane and octameric ring topologies. Reconstructions of both protein assemblies are in good agreement with crystallographic analyses of the catenane and ring forms of CS2 hydrolase.

Benzothiazole-2-sulfonamides react with an excess of hydroxylamine in aqueous solutions to form 2-hydroxybenzothiazole, sulfur dioxide, and the corresponding amine. Mechanistic studies that employ a combination of structure–reactivity relationships, oxygen labeling experiments, and (in)direct detection of intermediates and products reveal that the reaction proceeds via oxygen attack, and that oxygen incorporated in the 2-hydroxybenzothiazole product derives from hydroxylamine. The reaction, which is performed under mild conditions, can be used as a deprotection method for cleavage of benzothiazole-2-sulfonyl-protected amino acids.