Pub Date : 2024-08-01DOI: 10.1038/s42004-024-01244-w
Shreyas Ramachandran, Simão M. João, Hanwen Jin, Johannes Lischner
Hot electrons and holes generated from the decay of localised surface plasmons in metallic nanoparticles can be harnessed for applications in solar energy conversion and sensing. In this paper, we study the generation of hot carriers in large spherical gold-silver alloy nanoparticles using a recently developed atomistic modelling approach that combines a solution of Maxwell’s equations with large-scale tight-binding simulations. We find that hot-carrier properties depend sensitively on the alloy composition. Specifically, nanoparticles with a large gold fraction produce hot carriers under visible light illumination while nanoparticles with a large silver fraction require higher photon energies to produce hot carriers. Moreover, most hot carriers in nanoparticles with a large gold fraction originate from interband transitions which give rise to energetic holes and ‘cold’ electrons near the Fermi level. Increasing the silver fraction enhances the generation rate of hot carriers from intraband transitions which produce energetic electrons and ‘cold’ holes. These findings demonstrate that alloy composition is a powerful tuning parameter for the design of nanoparticles for applications in solar energy conversion and sensing that require precise control of hot-carrier properties. To accelerate the design of plasmonic alloy nanoparticles for application in solar energy conversion devices, a detailed understanding of their electronic structure is required. Here, the authors use an atomistic modelling approach that combines a solution of Maxwell’s equations with large-scale tight-binding simulations to study the generation of hot carriers in large spherical gold-silver alloy nanoparticles.
{"title":"Hot carriers from intra- and interband transitions in gold-silver alloy nanoparticles","authors":"Shreyas Ramachandran, Simão M. João, Hanwen Jin, Johannes Lischner","doi":"10.1038/s42004-024-01244-w","DOIUrl":"10.1038/s42004-024-01244-w","url":null,"abstract":"Hot electrons and holes generated from the decay of localised surface plasmons in metallic nanoparticles can be harnessed for applications in solar energy conversion and sensing. In this paper, we study the generation of hot carriers in large spherical gold-silver alloy nanoparticles using a recently developed atomistic modelling approach that combines a solution of Maxwell’s equations with large-scale tight-binding simulations. We find that hot-carrier properties depend sensitively on the alloy composition. Specifically, nanoparticles with a large gold fraction produce hot carriers under visible light illumination while nanoparticles with a large silver fraction require higher photon energies to produce hot carriers. Moreover, most hot carriers in nanoparticles with a large gold fraction originate from interband transitions which give rise to energetic holes and ‘cold’ electrons near the Fermi level. Increasing the silver fraction enhances the generation rate of hot carriers from intraband transitions which produce energetic electrons and ‘cold’ holes. These findings demonstrate that alloy composition is a powerful tuning parameter for the design of nanoparticles for applications in solar energy conversion and sensing that require precise control of hot-carrier properties. To accelerate the design of plasmonic alloy nanoparticles for application in solar energy conversion devices, a detailed understanding of their electronic structure is required. Here, the authors use an atomistic modelling approach that combines a solution of Maxwell’s equations with large-scale tight-binding simulations to study the generation of hot carriers in large spherical gold-silver alloy nanoparticles.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11294548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1038/s42004-024-01252-w
Péter Ábrányi-Balogh, Dávid Bajusz, Zoltán Orgován, Aaron B. Keeley, László Petri, Nikolett Péczka, Tibor Viktor Szalai, Gyula Pálfy, Márton Gadanecz, Emma K. Grant, Tímea Imre, Tamás Takács, Ivan Ranđelović, Marcell Baranyi, András Marton, Gitta Schlosser, Qirat F. Ashraf, Elvin D. de Araujo, Tamás Karancsi, László Buday, József Tóvári, András Perczel, Jacob T. Bush, György M. Keserű
Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRasG12D protein, and the yet unliganded N-terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. Fragment screening is a popular strategy for generating viable chemical starting points for drug targets, however, weak affinity to targets, as well as the exploration of the binding site, remain challenging. Here, the authors develop pharmacophore-optimized photoaffinity fragments that can effectively explore the available binding site and enable a high hit rate and better sensitivity.
{"title":"Mapping protein binding sites by photoreactive fragment pharmacophores","authors":"Péter Ábrányi-Balogh, Dávid Bajusz, Zoltán Orgován, Aaron B. Keeley, László Petri, Nikolett Péczka, Tibor Viktor Szalai, Gyula Pálfy, Márton Gadanecz, Emma K. Grant, Tímea Imre, Tamás Takács, Ivan Ranđelović, Marcell Baranyi, András Marton, Gitta Schlosser, Qirat F. Ashraf, Elvin D. de Araujo, Tamás Karancsi, László Buday, József Tóvári, András Perczel, Jacob T. Bush, György M. Keserű","doi":"10.1038/s42004-024-01252-w","DOIUrl":"10.1038/s42004-024-01252-w","url":null,"abstract":"Fragment screening is a popular strategy of generating viable chemical starting points especially for challenging targets. Although fragments provide a better coverage of chemical space and they have typically higher chance of binding, their weak affinity necessitates highly sensitive biophysical assays. Here, we introduce a screening concept that combines evolutionary optimized fragment pharmacophores with the use of a photoaffinity handle that enables high hit rates by LC-MS-based detection. The sensitivity of our screening protocol was further improved by a target-conjugated photocatalyst. We have designed, synthesized, and screened 100 diazirine-tagged fragments against three benchmark and three therapeutically relevant protein targets of different tractability. Our therapeutic targets included a conventional enzyme, the first bromodomain of BRD4, a protein-protein interaction represented by the oncogenic KRasG12D protein, and the yet unliganded N-terminal domain of the STAT5B transcription factor. We have discovered several fragment hits against all three targets and identified their binding sites via enzymatic digestion, structural studies and modeling. Our results revealed that this protocol outperforms screening traditional fully functionalized and photoaffinity fragments in better exploration of the available binding sites and higher hit rates observed for even difficult targets. Fragment screening is a popular strategy for generating viable chemical starting points for drug targets, however, weak affinity to targets, as well as the exploration of the binding site, remain challenging. Here, the authors develop pharmacophore-optimized photoaffinity fragments that can effectively explore the available binding site and enable a high hit rate and better sensitivity.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11292009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141859238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rotaxanes are typically prepared using covalent bonds to trap a wheel component onto an axle molecule, and rotaxane-type wheel–axle assembly using only noncovalent interactions has been far less explored. Here we show that a dinickel(II) metallomacrocycle forms two different types of wheel–axle assemblies with a dibenzylammonium axle molecule based only on noncovalent interactions. The non-threaded assembly was obtained by introduction of Ni2+ into the macrocycle before the complexation with the axle molecule (metal-first method). The non-threaded assembly was in rapid equilibrium with each of the components in solution. The threaded assembly was obtained by introduction of Ni2+ after the formation of a pseudorotaxane from the non-metalated wheel and the axle molecule (axle-first method). The threaded assembly was not in equilibrium with the dissociated species even though it was maintained only by noncovalent interactions. Thus, formation of one of the non-threaded and threaded wheel–axle assemblies over the other is governed by the assembly pathway. Mechanically interlocked rotaxanes are typically prepared using covalent bonds to trap a wheel component onto an axle molecule, and rotaxane-type wheel–axle assembly using only noncovalent interactions has been far less explored. Here, a dinickel(II) metallomacrocycle is found to form two different types of wheel–axle assemblies, with a dibenzylammonium axle molecule forming both non-threaded and rotaxane-type threaded assemblies, based only on noncovalent interactions, with formation of one over the other governed by the assembly pathway.
{"title":"Non-threaded and rotaxane-type threaded wheel–axle assemblies consisting of dinickel(II) metallomacrocycle and dibenzylammonium axle","authors":"Yoko Sakata, Seiya Kobayashi, Misato Yamamoto, Katsuya Doken, Mayu Kamezawa, Sachiko Yamaki, Shigehisa Akine","doi":"10.1038/s42004-024-01246-8","DOIUrl":"10.1038/s42004-024-01246-8","url":null,"abstract":"Rotaxanes are typically prepared using covalent bonds to trap a wheel component onto an axle molecule, and rotaxane-type wheel–axle assembly using only noncovalent interactions has been far less explored. Here we show that a dinickel(II) metallomacrocycle forms two different types of wheel–axle assemblies with a dibenzylammonium axle molecule based only on noncovalent interactions. The non-threaded assembly was obtained by introduction of Ni2+ into the macrocycle before the complexation with the axle molecule (metal-first method). The non-threaded assembly was in rapid equilibrium with each of the components in solution. The threaded assembly was obtained by introduction of Ni2+ after the formation of a pseudorotaxane from the non-metalated wheel and the axle molecule (axle-first method). The threaded assembly was not in equilibrium with the dissociated species even though it was maintained only by noncovalent interactions. Thus, formation of one of the non-threaded and threaded wheel–axle assemblies over the other is governed by the assembly pathway. Mechanically interlocked rotaxanes are typically prepared using covalent bonds to trap a wheel component onto an axle molecule, and rotaxane-type wheel–axle assembly using only noncovalent interactions has been far less explored. Here, a dinickel(II) metallomacrocycle is found to form two different types of wheel–axle assemblies, with a dibenzylammonium axle molecule forming both non-threaded and rotaxane-type threaded assemblies, based only on noncovalent interactions, with formation of one over the other governed by the assembly pathway.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1038/s42004-024-01251-x
Xiongjie Xiao, Qianqian Wang, Xin Chai, Xu Zhang, Bin Jiang, Maili Liu
Metabolomics plays a crucial role in understanding metabolic processes within biological systems. Using specific pulse sequences, NMR-based metabolomics detects small and macromolecular metabolites that are altered in blood samples. Here we proposed a method called spectral editing neural network, which can effectively edit and separate the spectral signals of small and macromolecules in 1H NMR spectra of serum and plasma based on the linewidth of the peaks. We applied the model to process the 1H NMR spectra of plasma and serum. The extracted small and macromolecular spectra were then compared with experimentally obtained relaxation-edited and diffusion-edited spectra. Correlation analysis demonstrated the quantitative capability of the model in the extracted small molecule signals from 1H NMR spectra. The principal component analysis showed that the spectra extracted by the model and those obtained by NMR spectral editing methods reveal similar group information, demonstrating the effectiveness of the model in signal extraction. 1H NMR-based metabolomics can detect small and macromolecular metabolites simultaneously from complex biological samples, however, signaling overlap remains a challenge for accurate molecular identification and quantification. Here, the authors develop a spectral editing neural network to effectively edit and separate the spectral signals of small and macromolecules in the 1H NMR spectra of serum and plasma based on the linewidth of the peaks.
{"title":"Using neural networks to obtain NMR spectra of both small and macromolecules from blood samples in a single experiment","authors":"Xiongjie Xiao, Qianqian Wang, Xin Chai, Xu Zhang, Bin Jiang, Maili Liu","doi":"10.1038/s42004-024-01251-x","DOIUrl":"10.1038/s42004-024-01251-x","url":null,"abstract":"Metabolomics plays a crucial role in understanding metabolic processes within biological systems. Using specific pulse sequences, NMR-based metabolomics detects small and macromolecular metabolites that are altered in blood samples. Here we proposed a method called spectral editing neural network, which can effectively edit and separate the spectral signals of small and macromolecules in 1H NMR spectra of serum and plasma based on the linewidth of the peaks. We applied the model to process the 1H NMR spectra of plasma and serum. The extracted small and macromolecular spectra were then compared with experimentally obtained relaxation-edited and diffusion-edited spectra. Correlation analysis demonstrated the quantitative capability of the model in the extracted small molecule signals from 1H NMR spectra. The principal component analysis showed that the spectra extracted by the model and those obtained by NMR spectral editing methods reveal similar group information, demonstrating the effectiveness of the model in signal extraction. 1H NMR-based metabolomics can detect small and macromolecular metabolites simultaneously from complex biological samples, however, signaling overlap remains a challenge for accurate molecular identification and quantification. Here, the authors develop a spectral editing neural network to effectively edit and separate the spectral signals of small and macromolecules in the 1H NMR spectra of serum and plasma based on the linewidth of the peaks.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1038/s42004-024-01243-x
Xiao-Ping Xu, Wenxiang Cao, Mark F. Swift, Nandan G. Pandit, Andrew E. Huehn, Charles V. Sindelar, Enrique M. De La Cruz, Dorit Hanein, Niels Volkmann
Actin filament assembly and the regulation of its mechanical properties are fundamental processes essential for eukaryotic cell function. Residue E167 in vertebrate actins forms an inter-subunit salt bridge with residue K61 of the adjacent subunit. Saccharomyces cerevisiae actin filaments are more flexible than vertebrate filaments and have an alanine at this position (A167). Substitution of this alanine for a glutamic acid (A167E) confers Saccharomyces cerevisiae actin filaments with salt-dependent stiffness similar to vertebrate actins. We developed an optimized cryogenic electron microscopy workflow refining sample preparation and vitrification to obtain near-atomic resolution structures of wild-type and A167E mutant Saccharomyces cerevisiae actin filaments. The difference between these structures allowed us to pinpoint the potential binding site of a filament-associated cation that controls the stiffness of the filaments in vertebrate and A167E Saccharomyces cerevisiae actins. Through an analysis of previously published high-resolution reconstructions of vertebrate actin filaments, along with a newly determined high-resolution vertebrate actin structure in the absence of potassium, we identified a unique peak near residue 167 consistent with the binding of a magnesium ion. Our findings show how magnesium can contribute to filament stiffening by directly bridging actin subunits and allosterically affecting the orientation of the DNase-I binding loop of actin, which plays a regulatory role in modulating actin filament stiffness and interactions with regulatory proteins. Actin filament assembly and the regulation of its mechanical properties are fundamental processes essential for eukaryotic cell function, however, the molecular mechanisms that govern the mechanical properties of the actin filaments formed from different species are not fully understood. Here, the authors report high-resolution cryo-EM reconstructions of yeast actin from Saccharomyces cerevisiae and propose how the mechanism of the stiffening of the actin filament is affected by magnesium cations.
{"title":"High-resolution yeast actin structures indicate the molecular mechanism of actin filament stiffening by cations","authors":"Xiao-Ping Xu, Wenxiang Cao, Mark F. Swift, Nandan G. Pandit, Andrew E. Huehn, Charles V. Sindelar, Enrique M. De La Cruz, Dorit Hanein, Niels Volkmann","doi":"10.1038/s42004-024-01243-x","DOIUrl":"10.1038/s42004-024-01243-x","url":null,"abstract":"Actin filament assembly and the regulation of its mechanical properties are fundamental processes essential for eukaryotic cell function. Residue E167 in vertebrate actins forms an inter-subunit salt bridge with residue K61 of the adjacent subunit. Saccharomyces cerevisiae actin filaments are more flexible than vertebrate filaments and have an alanine at this position (A167). Substitution of this alanine for a glutamic acid (A167E) confers Saccharomyces cerevisiae actin filaments with salt-dependent stiffness similar to vertebrate actins. We developed an optimized cryogenic electron microscopy workflow refining sample preparation and vitrification to obtain near-atomic resolution structures of wild-type and A167E mutant Saccharomyces cerevisiae actin filaments. The difference between these structures allowed us to pinpoint the potential binding site of a filament-associated cation that controls the stiffness of the filaments in vertebrate and A167E Saccharomyces cerevisiae actins. Through an analysis of previously published high-resolution reconstructions of vertebrate actin filaments, along with a newly determined high-resolution vertebrate actin structure in the absence of potassium, we identified a unique peak near residue 167 consistent with the binding of a magnesium ion. Our findings show how magnesium can contribute to filament stiffening by directly bridging actin subunits and allosterically affecting the orientation of the DNase-I binding loop of actin, which plays a regulatory role in modulating actin filament stiffness and interactions with regulatory proteins. Actin filament assembly and the regulation of its mechanical properties are fundamental processes essential for eukaryotic cell function, however, the molecular mechanisms that govern the mechanical properties of the actin filaments formed from different species are not fully understood. Here, the authors report high-resolution cryo-EM reconstructions of yeast actin from Saccharomyces cerevisiae and propose how the mechanism of the stiffening of the actin filament is affected by magnesium cations.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1038/s42004-024-01248-6
P. Merino, L. Martínez, G. Santoro, J. I. Martínez, K. Lauwaet, M. Accolla, N. Ruiz del Arbol, C. Sánchez-Sánchez, A. Martín-Jimenez, R. Otero, M. Piantek, D. Serrate, R. Lebrón-Aguilar, J. E. Quintanilla-López, J. Mendez, P. L. De Andres, J. A. Martín-Gago
Aliphatics prevail in asteroids, comets, meteorites and other bodies in our solar system. They are also found in the interstellar and circumstellar media both in gas-phase and in dust grains. Among aliphatics, linear alkanes (n-CnH2n+2) are known to survive in carbonaceous chondrites in hundreds to thousands of parts per billion, encompassing sequences from CH4 to n-C31H64. Despite being systematically detected, the mechanism responsible for their formation in meteorites has yet to be identified. Based on advanced laboratory astrochemistry simulations, we propose a gas-phase synthesis mechanism for n-alkanes starting from carbon and hydrogen under conditions of temperature and pressure that mimic those found in carbon-rich circumstellar envelopes. We characterize the analogs generated in a customized sputter gas aggregation source using a combination of atomically precise scanning tunneling microscopy, non-contact atomic force microscopy and ex-situ gas chromatography-mass spectrometry. Within the formed carbon nanostructures, we identify the presence of n-alkanes with sizes ranging from n-C8H18 to n-C32H66. Ab-initio calculations of formation free energies, kinetic barriers, and kinetic chemical network modelling lead us to propose a gas-phase growth mechanism for the formation of large n-alkanes based on methyl-methylene addition (MMA). In this process, methylene serves as both a reagent and a catalyst for carbon chain growth. Our study provides evidence of an aliphatic gas-phase synthesis mechanism around evolved stars and provides a potential explanation for its presence in interstellar dust and meteorites. Extraterrestrial organic matter found in meteorites may hold a unique record of its synthesis, and chemical and thermal alterations in the parent body, however, the origin of such aliphatics remains enigmatic. Here, the authors propose sequential gas-phase methyl-methylene addition growth of n-C8H18 to n-C32H66 alkanes based on a series of sputter gas aggregation source experiments and DFT calculations.
{"title":"n-Alkanes formed by methyl-methylene addition as a source of meteoritic aliphatics","authors":"P. Merino, L. Martínez, G. Santoro, J. I. Martínez, K. Lauwaet, M. Accolla, N. Ruiz del Arbol, C. Sánchez-Sánchez, A. Martín-Jimenez, R. Otero, M. Piantek, D. Serrate, R. Lebrón-Aguilar, J. E. Quintanilla-López, J. Mendez, P. L. De Andres, J. A. Martín-Gago","doi":"10.1038/s42004-024-01248-6","DOIUrl":"10.1038/s42004-024-01248-6","url":null,"abstract":"Aliphatics prevail in asteroids, comets, meteorites and other bodies in our solar system. They are also found in the interstellar and circumstellar media both in gas-phase and in dust grains. Among aliphatics, linear alkanes (n-CnH2n+2) are known to survive in carbonaceous chondrites in hundreds to thousands of parts per billion, encompassing sequences from CH4 to n-C31H64. Despite being systematically detected, the mechanism responsible for their formation in meteorites has yet to be identified. Based on advanced laboratory astrochemistry simulations, we propose a gas-phase synthesis mechanism for n-alkanes starting from carbon and hydrogen under conditions of temperature and pressure that mimic those found in carbon-rich circumstellar envelopes. We characterize the analogs generated in a customized sputter gas aggregation source using a combination of atomically precise scanning tunneling microscopy, non-contact atomic force microscopy and ex-situ gas chromatography-mass spectrometry. Within the formed carbon nanostructures, we identify the presence of n-alkanes with sizes ranging from n-C8H18 to n-C32H66. Ab-initio calculations of formation free energies, kinetic barriers, and kinetic chemical network modelling lead us to propose a gas-phase growth mechanism for the formation of large n-alkanes based on methyl-methylene addition (MMA). In this process, methylene serves as both a reagent and a catalyst for carbon chain growth. Our study provides evidence of an aliphatic gas-phase synthesis mechanism around evolved stars and provides a potential explanation for its presence in interstellar dust and meteorites. Extraterrestrial organic matter found in meteorites may hold a unique record of its synthesis, and chemical and thermal alterations in the parent body, however, the origin of such aliphatics remains enigmatic. Here, the authors propose sequential gas-phase methyl-methylene addition growth of n-C8H18 to n-C32H66 alkanes based on a series of sputter gas aggregation source experiments and DFT calculations.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-29DOI: 10.1038/s42004-024-01249-5
Qijiang Shu, Fuhua Yang, Zedong Lin, Linjing Yang, Zhan Wang, Donghai Ye, Zhi Dong, Pengru Huang, Wenping Wang
Global changes and drug abuse are forcing humanity to face various disease problems, and alternative therapies with safe natural substances have important research value. This paper combines various techniques in quantum chemical calculations and molecular simulations to provide molecular-level insight into the dynamics of the self-assembly of N-isopropylacrylamide (NIPAM) for loading curcumin (CUR). The results indicate that increasing the chain length of NIPAM molecules reduces their efficiency in encapsulating and locking CUR, and electrostatic interactions and van der Waals interactions are the main driving forces behind the evolution of system configurations in these processes. The isopropyl groups of NIPAM and the two phenolic ring planes of CUR are the main contact areas for the interaction between the two types of molecules. The thermosensitive effect of NIPAM can alter the distribution of isopropyl groups in NIPAM molecules around CUR. As a result, when the temperature rises from ambient temperature (300 K) to human characteristic temperature (310 K), the NIPAM-CUR interactions and radial distribution functions suggest that body temperature is more suitable for drug release. Our findings offer a vital theoretical foundation and practical guidance for researchers to develop temperature-sensitive drug delivery systems tailored for CUR, addressing its clinical application bottleneck. Curcumin is a natural substance with beneficial pharmacological properties, but its poor solubility, instability and poor absorption hinder its use as a therapeutic agent in the body. Here, the authors use quantum chemical calculations and molecular simulations to explore the self-assembly of N-isopropylacrylamide for its use in the loading and release of curcumin.
全球变化和药物滥用迫使人类面临各种疾病问题，利用安全的天然物质进行替代疗法具有重要的研究价值。本文结合量子化学计算和分子模拟等多种技术，从分子层面深入探讨了 N-isopropylacrylamide (NIPAM) 在负载姜黄素（CUR）时的自组装动力学。研究结果表明，增加 NIPAM 分子链的长度会降低它们封装和锁定姜黄素的效率，而静电相互作用和范德华相互作用是这些过程中系统构型演变的主要驱动力。NIPAM 的异丙基基团和 CUR 的两个酚环平面是两类分子相互作用的主要接触区域。NIPAM 的热敏效应可改变 CUR 周围 NIPAM 分子中异丙基的分布。因此，当温度从环境温度（300 K）升至人体特征温度（310 K）时，NIPAM-CUR 的相互作用和径向分布函数表明体温更适合药物释放。我们的研究结果为研究人员开发适合 CUR 的温度敏感型给药系统提供了重要的理论基础和实践指导，解决了 CUR 临床应用的瓶颈问题。
{"title":"Molecular understanding of the self-assembly of an N-isopropylacrylamide delivery system for the loading and temperature-dependent release of curcumin","authors":"Qijiang Shu, Fuhua Yang, Zedong Lin, Linjing Yang, Zhan Wang, Donghai Ye, Zhi Dong, Pengru Huang, Wenping Wang","doi":"10.1038/s42004-024-01249-5","DOIUrl":"10.1038/s42004-024-01249-5","url":null,"abstract":"Global changes and drug abuse are forcing humanity to face various disease problems, and alternative therapies with safe natural substances have important research value. This paper combines various techniques in quantum chemical calculations and molecular simulations to provide molecular-level insight into the dynamics of the self-assembly of N-isopropylacrylamide (NIPAM) for loading curcumin (CUR). The results indicate that increasing the chain length of NIPAM molecules reduces their efficiency in encapsulating and locking CUR, and electrostatic interactions and van der Waals interactions are the main driving forces behind the evolution of system configurations in these processes. The isopropyl groups of NIPAM and the two phenolic ring planes of CUR are the main contact areas for the interaction between the two types of molecules. The thermosensitive effect of NIPAM can alter the distribution of isopropyl groups in NIPAM molecules around CUR. As a result, when the temperature rises from ambient temperature (300 K) to human characteristic temperature (310 K), the NIPAM-CUR interactions and radial distribution functions suggest that body temperature is more suitable for drug release. Our findings offer a vital theoretical foundation and practical guidance for researchers to develop temperature-sensitive drug delivery systems tailored for CUR, addressing its clinical application bottleneck. Curcumin is a natural substance with beneficial pharmacological properties, but its poor solubility, instability and poor absorption hinder its use as a therapeutic agent in the body. Here, the authors use quantum chemical calculations and molecular simulations to explore the self-assembly of N-isopropylacrylamide for its use in the loading and release of curcumin.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11289375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-24DOI: 10.1038/s42004-024-01245-9
Nnanna Ukoji, Danny Rodriguez, Huiyao Kuang, Serge Desgreniers, John S. Tse
The high-pressure structures of K-Ag alloys were examples of pressure-induced electron transfer from the electropositive potassium to the electronegative silver. We re-examined the crystal and electronic structures of KAg2, K2Ag, and K3Ag using powder X-ray diffraction and theoretical calculations. Our findings establish a connection between the morphologies of these three phases and the precursor face-centered cubic Ag. For K2Ag, we discovered a disordered structure that better matches the X-ray pattern. Valence electron density distributions obtained from the maximum entropy method, along with charge density calculations, provide a comprehensive understanding of the evolution of chemical bonding in these systems. It was found that K atoms share their valence electrons during alloy formation, contributing to K-Ag and Ag-Ag bonds in K2Ag and KAg2, while no Ag-Ag bonds are present in K3Ag. These results indicate the Zintl-Klemm model may be too simplistic to describe the structure and bonding in high-pressure binary intermetallic compounds. The Zintl-Klemm concept explains the structure and chemical bonding of intermetallic compounds at high pressures — such as high-temperature superconducting metal superhydrides. Here, the authors elucidate the electronic structures of three high-pressure potassium silver alloys, providing an example of where the Zint-Klemm concept needs to be expanded.
{"title":"Structure and chemical bonding in high-pressure potassium silver alloys","authors":"Nnanna Ukoji, Danny Rodriguez, Huiyao Kuang, Serge Desgreniers, John S. Tse","doi":"10.1038/s42004-024-01245-9","DOIUrl":"10.1038/s42004-024-01245-9","url":null,"abstract":"The high-pressure structures of K-Ag alloys were examples of pressure-induced electron transfer from the electropositive potassium to the electronegative silver. We re-examined the crystal and electronic structures of KAg2, K2Ag, and K3Ag using powder X-ray diffraction and theoretical calculations. Our findings establish a connection between the morphologies of these three phases and the precursor face-centered cubic Ag. For K2Ag, we discovered a disordered structure that better matches the X-ray pattern. Valence electron density distributions obtained from the maximum entropy method, along with charge density calculations, provide a comprehensive understanding of the evolution of chemical bonding in these systems. It was found that K atoms share their valence electrons during alloy formation, contributing to K-Ag and Ag-Ag bonds in K2Ag and KAg2, while no Ag-Ag bonds are present in K3Ag. These results indicate the Zintl-Klemm model may be too simplistic to describe the structure and bonding in high-pressure binary intermetallic compounds. The Zintl-Klemm concept explains the structure and chemical bonding of intermetallic compounds at high pressures — such as high-temperature superconducting metal superhydrides. Here, the authors elucidate the electronic structures of three high-pressure potassium silver alloys, providing an example of where the Zint-Klemm concept needs to be expanded.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Globally, millions of diabetic patients require daily life-saving insulin injections. Insulin heat-lability and fibrillation pose significant challenges, especially in parts of the world without ready access to uninterrupted refrigeration. Here, we have synthesized four human insulin analogs by conjugating ε-amine of B29 lysine of insulin with acetic acid, phenylacetic acid, alanine, and phenylalanine residues. Of these, phenylalanine-conjugated insulin, termed FHI, was the most stable under high temperature (65 °C), elevated salt stress (25 mM NaCl), and varying pH levels (ranging from highly acidic pH 1.6 to physiological pH 7.4). It resists fibrillation for a significantly longer duration with sustained biological activity in in vitro, ex vivo, and in vivo and displays prolonged stability over its native counterpart. We further unravel the critical interactions, such as additional aromatic π-π interactions and hydrogen bonding in FHI, that are notably absent in native insulin. These interactions confer enhanced structural stability of FHI and offer a promising solution to the challenges associated with insulin heat sensitivity. Heat-lability and fibrillation of insulin pose significant challenges for insulin storage. Here, the authors report chemically modified analogs of insulin by functionalizing the ε-amine group of B29 Lys with phenylalanine, to improve insulin thermostability and resist fibrillation while maintaining robust in vivo activity.
{"title":"Synthesis of a highly thermostable insulin by phenylalanine conjugation at B29 Lysine","authors":"Shantanu Sen, Rafat Ali, Akanksha Onkar, Shivani Verma, Quazi Taushif Ahmad, Pratibha Bhadauriya, Pradip Sinha, Nisanth N. Nair, Subramaniam Ganesh, Sandeep Verma","doi":"10.1038/s42004-024-01241-z","DOIUrl":"10.1038/s42004-024-01241-z","url":null,"abstract":"Globally, millions of diabetic patients require daily life-saving insulin injections. Insulin heat-lability and fibrillation pose significant challenges, especially in parts of the world without ready access to uninterrupted refrigeration. Here, we have synthesized four human insulin analogs by conjugating ε-amine of B29 lysine of insulin with acetic acid, phenylacetic acid, alanine, and phenylalanine residues. Of these, phenylalanine-conjugated insulin, termed FHI, was the most stable under high temperature (65 °C), elevated salt stress (25 mM NaCl), and varying pH levels (ranging from highly acidic pH 1.6 to physiological pH 7.4). It resists fibrillation for a significantly longer duration with sustained biological activity in in vitro, ex vivo, and in vivo and displays prolonged stability over its native counterpart. We further unravel the critical interactions, such as additional aromatic π-π interactions and hydrogen bonding in FHI, that are notably absent in native insulin. These interactions confer enhanced structural stability of FHI and offer a promising solution to the challenges associated with insulin heat sensitivity. Heat-lability and fibrillation of insulin pose significant challenges for insulin storage. Here, the authors report chemically modified analogs of insulin by functionalizing the ε-amine group of B29 Lys with phenylalanine, to improve insulin thermostability and resist fibrillation while maintaining robust in vivo activity.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11266353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-21DOI: 10.1038/s42004-024-01242-y
Youngchang Kim, Seung Hwan Lee, Priyanka Gade, Maren Nattermann, Natalia Maltseva, Michael Endres, Jing Chen, Philipp Wichmann, Yang Hu, Daniel G. Marchal, Yasuo Yoshikuni, Tobias J. Erb, Ramon Gonzalez, Karolina Michalska, Andrzej Joachimiak
2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is a thiamine diphosphate (ThDP)-dependent versatile enzyme originally discovered in the mammalian α-oxidation pathway. HACL/S natively cleaves 2-hydroxyacyl-CoAs and, in its reverse direction, condenses formyl-CoA with aldehydes or ketones. The one-carbon elongation biochemistry based on HACL/S has enabled the use of molecules derived from greenhouse gases as biomanufacturing feedstocks. We investigated several HACL/S family members with high activity in the condensation of formyl-CoA and aldehydes, and distinct chain-length specificities and kinetic parameters. Our analysis revealed the structures of enzymes in complex with acyl-CoA substrates and products, several covalent intermediates, bound ThDP and ADP, as well as the C-terminal active site region. One of these observed states corresponds to the intermediary α–carbanion with hydroxymethyl-CoA covalently attached to ThDP. This research distinguishes HACL/S from related sub-families and identifies key residues involved in substrate binding and catalysis. These findings expand our knowledge of acyloin-condensation biochemistry and offer attractive prospects for biocatalysis using carbon elongation. 2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is known to catalyze the condensation of formyl-CoA with aldehydes or ketones, however, the mechanism of one-carbon elongation biochemistry is not well understood. Here, the authors report the structures of enzymes in complex with co-factors, substrates, and products, revealing key intermediates and the C-terminal active site region, and distinguishing them from related sub-families.
{"title":"Revealing reaction intermediates in one-carbon elongation by thiamine diphosphate/CoA-dependent enzyme family","authors":"Youngchang Kim, Seung Hwan Lee, Priyanka Gade, Maren Nattermann, Natalia Maltseva, Michael Endres, Jing Chen, Philipp Wichmann, Yang Hu, Daniel G. Marchal, Yasuo Yoshikuni, Tobias J. Erb, Ramon Gonzalez, Karolina Michalska, Andrzej Joachimiak","doi":"10.1038/s42004-024-01242-y","DOIUrl":"10.1038/s42004-024-01242-y","url":null,"abstract":"2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is a thiamine diphosphate (ThDP)-dependent versatile enzyme originally discovered in the mammalian α-oxidation pathway. HACL/S natively cleaves 2-hydroxyacyl-CoAs and, in its reverse direction, condenses formyl-CoA with aldehydes or ketones. The one-carbon elongation biochemistry based on HACL/S has enabled the use of molecules derived from greenhouse gases as biomanufacturing feedstocks. We investigated several HACL/S family members with high activity in the condensation of formyl-CoA and aldehydes, and distinct chain-length specificities and kinetic parameters. Our analysis revealed the structures of enzymes in complex with acyl-CoA substrates and products, several covalent intermediates, bound ThDP and ADP, as well as the C-terminal active site region. One of these observed states corresponds to the intermediary α–carbanion with hydroxymethyl-CoA covalently attached to ThDP. This research distinguishes HACL/S from related sub-families and identifies key residues involved in substrate binding and catalysis. These findings expand our knowledge of acyloin-condensation biochemistry and offer attractive prospects for biocatalysis using carbon elongation. 2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is known to catalyze the condensation of formyl-CoA with aldehydes or ketones, however, the mechanism of one-carbon elongation biochemistry is not well understood. Here, the authors report the structures of enzymes in complex with co-factors, substrates, and products, revealing key intermediates and the C-terminal active site region, and distinguishing them from related sub-families.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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