JACS Au最新文献

Structure flexibility is essential for the biological function of proteins. At the same time, many proteins need to discriminate ligands with subtle differences, with one example being ion selectivity. Investigating the mechanisms by which flexible proteins achieve such precise discrimination is crucial for advancing our understanding of their functions. In this work, we study transporter KCC4, which undergoes continuous conformation changes during ion transport and can realize K⁺ over Na⁺ selectivity. Our findings reveal that the center of the binding site no longer represents a stable equilibrium for the undesired Na⁺, and its binding mode exhibits bifurcation. Interestingly, protein conformation fluctuation can induce collective behavior throughout the entire binding region, which contributes to this bifurcation. Thus, the symmetry of the binding mode decreases from the inherent T_d symmetry to a C_2v symmetry, and the binding stability of Na⁺ is largely reduced. A similar phenomenon is observed in a GPCR, β₂-AR, where a less favored ligand forms a biased binding mode with reduced stability. The mechanism underlying the selectivity in such flexible regions could be interpreted as spontaneous symmetry breaking, which may represent a general mechanism by which flexible proteins achieve efficient ligand discrimination.

Structure flexibility is essential for the biological function of proteins. At the same time, many proteins need to discriminate ligands with subtle differences, with one example being ion selectivity. Investigating the mechanisms by which flexible proteins achieve such precise discrimination is crucial for advancing our understanding of their functions. In this work, we study transporter KCC4, which undergoes continuous conformation changes during ion transport and can realize K⁺ over Na⁺ selectivity. Our findings reveal that the center of the binding site no longer represents a stable equilibrium for the undesired Na⁺, and its binding mode exhibits bifurcation. Interestingly, protein conformation fluctuation can induce collective behavior throughout the entire binding region, which contributes to this bifurcation. Thus, the symmetry of the binding mode decreases from the inherent T _d symmetry to a C_2v symmetry, and the binding stability of Na⁺ is largely reduced. A similar phenomenon is observed in a GPCR, β₂-AR, where a less favored ligand forms a biased binding mode with reduced stability. The mechanism underlying the selectivity in such flexible regions could be interpreted as spontaneous symmetry breaking, which may represent a general mechanism by which flexible proteins achieve efficient ligand discrimination.

Fluorinated molecules are of paramount importance because of their unique properties. As a result, the search for innovative approaches to the synthesis of this class of compounds has been relentless over the years. Among these, the combination of photocatalysis and organofluorine chemistry turned out to be an effective partnership to access unattainable fluorinated molecules. This Perspective provides an overview of the recent advances in synthesizing fluorinated molecules via an organophotoredox-catalyzed defluorination process from trifluoromethylated compounds. It encompasses the preparation of difluoromethylated (hetero)arenes, amides, and esters as well as gem-difluoroalkene derivatives using C(sp³)–F bond activation or β-fragmentation. This Perspective will highlight remaining challenges and discuss future research opportunities.

Fluorinated molecules are of paramount importance because of their unique properties. As a result, the search for innovative approaches to the synthesis of this class of compounds has been relentless over the years. Among these, the combination of photocatalysis and organofluorine chemistry turned out to be an effective partnership to access unattainable fluorinated molecules. This Perspective provides an overview of the recent advances in synthesizing fluorinated molecules via an organophotoredox-catalyzed defluorination process from trifluoromethylated compounds. It encompasses the preparation of difluoromethylated (hetero)arenes, amides, and esters as well as gem-difluoroalkene derivatives using C(sp³)-F bond activation or β-fragmentation. This Perspective will highlight remaining challenges and discuss future research opportunities.

The positron emission tomography (PET) tracer 2-deoxy-2-[¹⁸F]fluoroglucose ([¹⁸F]FDG) is widely used to study diseases where glucose metabolism is dysregulated, including cancer and neurodegenerative disorders. Here we investigate the hypothesis that the 2-position deuterium-enriched analogue 2-deoxy-2-[²H₂]-d-glucose (2-DG-d2) can also map glucose uptake using deuterium metabolic imaging (DMI) without ionizing radiation. To accomplish this, we used a spectrally selective multiband radiofrequency pulse and balanced steady-state free procession (bSSFP) technique, enabling rapid ²H imaging with high specificity and sensitivity to 2-DG-d2. Both in vitro and in vivo validations demonstrated the sequence’s ability to suppress endogenous water signal. Mapping of 2-DG-d2 with high spatial resolution was achieved in healthy mouse brains, comparable to what might be obtained using [¹⁸F]FDG PET. The numerous applications of [¹⁸F]FDG PET, as well as recent clinical translation of the natural abundance 2-deoxy-d-glucose (2-DG) parent sugar, suggest that DMI using 2-DG-d2 may be applied to patients in the future.

This Perspective deals with the organic chemistry of alkynyl radicals, a species that is ultimately still little known in the synthetic community. Starting with the first observations and characterizations of alkynyl radicals generated by various methodologies in the gas phase, we then particularly turned our attention to the implications of these highly reactive intermediates in organic synthesis and materials science. Mechanistic considerations have been provided, in particular, for the key steps of generating alkynyl radicals, which are mainly based on photochemical or thermal activation and single electron transfer processes. This Perspective should serve as a roadmap for the synthetic chemist in order to plan more reliably alkynylation reactions based on alkynyl radicals.

Electrocatalysis, which leverages renewable electricity, has emerged as a cornerstone technology in the transition toward sustainable energy and chemical production. However, traditional electrocatalytic systems often produce mixed, impure products, necessitating costly purification. Solid-state electrolyte (SSE) reactors represent a transformative advancement by enabling the direct production of high-purity chemicals, significantly reducing purification costs and energy consumption. The versatility of SSE reactors extends to applications such as CO₂ capture and tandem reactions, aligning with the green and decentralized production paradigm. This Perspective provides a comprehensive overview of SSE reactors, discussing their principles, design innovations, and applications in producing pure chemicals-such as liquid carbon fuels, hydrogen peroxide, and ammonia-directly from CO₂ and other sources. We further explore the potential of SSE reactors in applications such as CO₂ capture and tandem reactions, highlighting their compatibility with versatile production systems. Finally, we outline future research directions for SSE reactors, underscoring their role in advancing sustainable chemical manufacturing.

A protocol was developed for the large-scale preparation (nearly 200 g per batch) of (CF₃S)₂C═S. The synthesis of gem-bis(trifluoromethylthio)alkenes was achieved through the Barton–Kellogg reaction, without the involvement of trivalent phosphines. With slight modifications to the reaction conditions, the synthesis of gem-bis(trifluoromethylthio)cyclopropanes, which are difficult to obtain by other methods, can be realized. Due to the large steric hindrance of the trifluoromethylthio group, the CF₃S group may be positioned close to the trans-substituent rather than the cis-substituent in cyclopropanes, as confirmed by single-crystal X-ray analysis, contributing to unique NMR structural characteristics. Further investigation into the reaction mechanism revealed the unique reactivity of the double bond in gem-bis(trifluoromethylthio)alkenes.

A protocol was developed for the large-scale preparation (nearly 200 g per batch) of (CF₃S)₂C=S. The synthesis of gem-bis(trifluoromethylthio)alkenes was achieved through the Barton-Kellogg reaction, without the involvement of trivalent phosphines. With slight modifications to the reaction conditions, the synthesis of gem-bis(trifluoromethylthio)cyclopropanes, which are difficult to obtain by other methods, can be realized. Due to the large steric hindrance of the trifluoromethylthio group, the CF₃S group may be positioned close to the trans-substituent rather than the cis-substituent in cyclopropanes, as confirmed by single-crystal X-ray analysis, contributing to unique NMR structural characteristics. Further investigation into the reaction mechanism revealed the unique reactivity of the double bond in gem-bis(trifluoromethylthio)alkenes.

This Perspective deals with the organic chemistry of alkynyl radicals, a species that is ultimately still little known in the synthetic community. Starting with the first observations and characterizations of alkynyl radicals generated by various methodologies in the gas phase, we then particularly turned our attention to the implications of these highly reactive intermediates in organic synthesis and materials science. Mechanistic considerations have been provided, in particular, for the key steps of generating alkynyl radicals, which are mainly based on photochemical or thermal activation and single electron transfer processes. This Perspective should serve as a roadmap for the synthetic chemist in order to plan more reliably alkynylation reactions based on alkynyl radicals.