Pub Date : 2024-11-12DOI: 10.1038/s42004-024-01338-5
Enebie Ramos Cáceres, Lotte Kemperman, Kimberly M. Bonger
Myeloperoxidase (MPO) plays an important role in the immune response of human neutrophils and has been implicated in autoimmune conditions, cardiovascular disorders, and neurodegeneration. Current methods to detect MPO activity rely on the detection of HOCl using activatable probes or require challenging experimental procedures. Therefore, these tools provide limited information about the dynamics and localization of MPO in complex molecular processes such as NETosis in real time. In this study, we report a ‘’turn-on” activity-based probe that fluoresces exclusively upon binding to MPO, exhibits minimal background fluorescence in buffered aqueous media, and is blocked by MPO inhibitors. Our probe facilitates real-time imaging of direct MPO activity in human neutrophils and HL-60-derived granulocytes during NETosis under wash-free conditions. Furthermore, it allows for the discrimination between different triggers of NETosis in human neutrophils. These findings hold promise for advancing our understanding of the role of MPO in immune responses and inflammatory conditions. Myeloperoxidase (MPO) plays an important role in the innate immune response of human neutrophils and has been implicated in various diseases, but current methods to detect MPO provide limited information about its dynamics and localization in complex molecular processes. Here, the authors develop an activity-based probe that fluoresces exclusively upon binding to MPO, enabling real-time imaging of direct intracellular MPO activity in human neutrophils and HL-60-derived granulocytes during NETosis under wash-free conditions.
{"title":"Environment-sensitive turn-on fluorescent probe enables live cell imaging of myeloperoxidase activity during NETosis","authors":"Enebie Ramos Cáceres, Lotte Kemperman, Kimberly M. Bonger","doi":"10.1038/s42004-024-01338-5","DOIUrl":"10.1038/s42004-024-01338-5","url":null,"abstract":"Myeloperoxidase (MPO) plays an important role in the immune response of human neutrophils and has been implicated in autoimmune conditions, cardiovascular disorders, and neurodegeneration. Current methods to detect MPO activity rely on the detection of HOCl using activatable probes or require challenging experimental procedures. Therefore, these tools provide limited information about the dynamics and localization of MPO in complex molecular processes such as NETosis in real time. In this study, we report a ‘’turn-on” activity-based probe that fluoresces exclusively upon binding to MPO, exhibits minimal background fluorescence in buffered aqueous media, and is blocked by MPO inhibitors. Our probe facilitates real-time imaging of direct MPO activity in human neutrophils and HL-60-derived granulocytes during NETosis under wash-free conditions. Furthermore, it allows for the discrimination between different triggers of NETosis in human neutrophils. These findings hold promise for advancing our understanding of the role of MPO in immune responses and inflammatory conditions. Myeloperoxidase (MPO) plays an important role in the innate immune response of human neutrophils and has been implicated in various diseases, but current methods to detect MPO provide limited information about its dynamics and localization in complex molecular processes. Here, the authors develop an activity-based probe that fluoresces exclusively upon binding to MPO, enabling real-time imaging of direct intracellular MPO activity in human neutrophils and HL-60-derived granulocytes during NETosis under wash-free conditions.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-7"},"PeriodicalIF":5.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01338-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600840","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 : 2024-11-12DOI: 10.1038/s42004-024-01357-2
Michael Landreh, Hannah Osterholz, Gefei Chen, Stefan D. Knight, Anna Rising, Axel Leppert
Liquid-liquid phase separation (LLPS) of proteins can be considered an intermediate solubility regime between disperse solutions and solid fibers. While LLPS has been described for several pathogenic amyloids, recent evidence suggests that it is similarly relevant for functional amyloids. Here, we review the evidence that links spider silk proteins (spidroins) and LLPS and its role in the spinning process. Major ampullate spidroins undergo LLPS mediated by stickers and spacers in their repeat regions. During spinning, the spidroins droplets shift from liquid to crystalline states. Shear force, altered ion composition, and pH changes cause micelle-like spidroin assemblies to form an increasingly ordered liquid-crystalline phase. Interactions between polyalanine regions in the repeat regions ultimately yield the characteristic β-crystalline structure of mature dragline silk fibers. Based on these findings, we hypothesize that liquid-liquid crystalline phase separation (LLCPS) can describe the molecular and macroscopic features of the phase transitions of major ampullate spidroins during spinning and speculate whether other silk types may use a similar mechanism to convert from liquid dope to solid fiber. Liquid-liquid phase separation (LLPS) of proteins can be considered an intermediate solubility regime between disperse solutions and solid fibers, relevant to both pathogenic and functional amyloids. Here, the authors review the evidence that links spider silk proteins (spidroins) and LLPS and its role in the spinning process.
{"title":"Liquid-liquid crystalline phase separation of spider silk proteins","authors":"Michael Landreh, Hannah Osterholz, Gefei Chen, Stefan D. Knight, Anna Rising, Axel Leppert","doi":"10.1038/s42004-024-01357-2","DOIUrl":"10.1038/s42004-024-01357-2","url":null,"abstract":"Liquid-liquid phase separation (LLPS) of proteins can be considered an intermediate solubility regime between disperse solutions and solid fibers. While LLPS has been described for several pathogenic amyloids, recent evidence suggests that it is similarly relevant for functional amyloids. Here, we review the evidence that links spider silk proteins (spidroins) and LLPS and its role in the spinning process. Major ampullate spidroins undergo LLPS mediated by stickers and spacers in their repeat regions. During spinning, the spidroins droplets shift from liquid to crystalline states. Shear force, altered ion composition, and pH changes cause micelle-like spidroin assemblies to form an increasingly ordered liquid-crystalline phase. Interactions between polyalanine regions in the repeat regions ultimately yield the characteristic β-crystalline structure of mature dragline silk fibers. Based on these findings, we hypothesize that liquid-liquid crystalline phase separation (LLCPS) can describe the molecular and macroscopic features of the phase transitions of major ampullate spidroins during spinning and speculate whether other silk types may use a similar mechanism to convert from liquid dope to solid fiber. Liquid-liquid phase separation (LLPS) of proteins can be considered an intermediate solubility regime between disperse solutions and solid fibers, relevant to both pathogenic and functional amyloids. Here, the authors review the evidence that links spider silk proteins (spidroins) and LLPS and its role in the spinning process.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-8"},"PeriodicalIF":5.9,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01357-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600845","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 : 2024-11-11DOI: 10.1038/s42004-024-01346-5
Ruoqi Yang, Hao Zhou, Fan Wang, Guangfu Yang
Fragment-Based Drug Design (FBDD) plays a pivotal role in the field of drug discovery and development. The construction of high-quality fragment libraries is a critical step in FBDD. Conventional fragmentation approaches often rely on rigid rules and chemical intuition, limiting their adaptability to diverse molecular structures. The rapid development of Artificial Intelligence (AI) technology offers a transformative opportunity to rethink traditional methods. Here, we present DigFrag, a digital fragmentation method that highlights important substructures by focusing locally within the molecular graph. In addition, we feed the fragments segmented by machine intelligence and human expertise into the deep generative model to compare the preference for data from different sources. Experimental results show that the structural diversity of fragments segmented by DigFrag is higher, and more desirable compounds are generated based on these fragments. These results also demonstrate that data generated based on AI methods may be more suitable for AI models. Moreover, a user-friendly platform called MolFrag ( https://dpai.ccnu.edu.cn/MolFrag/ ) is developed based on various fragmentation techniques to support molecular segmentation. Fragment-based drug design plays a pivotal role in the field of drug discovery and development, however, the construction of high-quality fragment libraries is a critical but challenging step. Here, the authors develop DigFrag, a digital fragmentation method based on the graph attention mechanism, showing higher structural diversity of the fragments and higher applicability to artificial intelligence-based drug design.
{"title":"DigFrag as a digital fragmentation method used for artificial intelligence-based drug design","authors":"Ruoqi Yang, Hao Zhou, Fan Wang, Guangfu Yang","doi":"10.1038/s42004-024-01346-5","DOIUrl":"10.1038/s42004-024-01346-5","url":null,"abstract":"Fragment-Based Drug Design (FBDD) plays a pivotal role in the field of drug discovery and development. The construction of high-quality fragment libraries is a critical step in FBDD. Conventional fragmentation approaches often rely on rigid rules and chemical intuition, limiting their adaptability to diverse molecular structures. The rapid development of Artificial Intelligence (AI) technology offers a transformative opportunity to rethink traditional methods. Here, we present DigFrag, a digital fragmentation method that highlights important substructures by focusing locally within the molecular graph. In addition, we feed the fragments segmented by machine intelligence and human expertise into the deep generative model to compare the preference for data from different sources. Experimental results show that the structural diversity of fragments segmented by DigFrag is higher, and more desirable compounds are generated based on these fragments. These results also demonstrate that data generated based on AI methods may be more suitable for AI models. Moreover, a user-friendly platform called MolFrag ( https://dpai.ccnu.edu.cn/MolFrag/ ) is developed based on various fragmentation techniques to support molecular segmentation. Fragment-based drug design plays a pivotal role in the field of drug discovery and development, however, the construction of high-quality fragment libraries is a critical but challenging step. Here, the authors develop DigFrag, a digital fragmentation method based on the graph attention mechanism, showing higher structural diversity of the fragments and higher applicability to artificial intelligence-based drug design.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-9"},"PeriodicalIF":5.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01346-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599026","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 : 2024-11-11DOI: 10.1038/s42004-024-01349-2
Vitaly V. Kuznetsov, Frederic Poineau, Konstantin E. German, Elena A. Filatova
The radioelement Technetium (element 43) pertains to various domains including the nuclear enterprise (i.e., spent nuclear fuel (SNF) reprocessing and nuclear waste remediation) and nuclear medicine (i.e., development of new imaging agents) as well as to the fundamental science of transition metals (i.e., chemical trends in catalytic properties). One method that can provide critical information to improve knowledge in these domains is 99Tc nuclear magnetic resonance (NMR) spectroscopy. The review, presented here, summarizes the pivotal role of 99Tc NMR spectroscopy over the past two decades and presents prospects of the method to tackle challenges in Tc chemistry. The radioelement technetium is central in spent nuclear fuel reprocessing and waste remediation, the development of new imaging agents, as well as in fundamental science of transition metals. Here, the authors review the pivotal role of 99Tc NMR spectroscopy over the past two decades and present prospects of the method to tackle challenges in Tc chemistry.
{"title":"Pivotal role of 99Tc NMR spectroscopy in solid-state and molecular chemistry","authors":"Vitaly V. Kuznetsov, Frederic Poineau, Konstantin E. German, Elena A. Filatova","doi":"10.1038/s42004-024-01349-2","DOIUrl":"10.1038/s42004-024-01349-2","url":null,"abstract":"The radioelement Technetium (element 43) pertains to various domains including the nuclear enterprise (i.e., spent nuclear fuel (SNF) reprocessing and nuclear waste remediation) and nuclear medicine (i.e., development of new imaging agents) as well as to the fundamental science of transition metals (i.e., chemical trends in catalytic properties). One method that can provide critical information to improve knowledge in these domains is 99Tc nuclear magnetic resonance (NMR) spectroscopy. The review, presented here, summarizes the pivotal role of 99Tc NMR spectroscopy over the past two decades and presents prospects of the method to tackle challenges in Tc chemistry. The radioelement technetium is central in spent nuclear fuel reprocessing and waste remediation, the development of new imaging agents, as well as in fundamental science of transition metals. Here, the authors review the pivotal role of 99Tc NMR spectroscopy over the past two decades and present prospects of the method to tackle challenges in Tc chemistry.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-13"},"PeriodicalIF":5.9,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01349-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142600876","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 : 2024-11-09DOI: 10.1038/s42004-024-01350-9
Kostiantyn V. Kravchyk, Huanyu Zhang, Maksym V. Kovalenko
Research on the Li7La3Zr2O12 (LLZO)/Li interface is essential for improving the performance of LLZO-based solid-state batteries. In this comment, the authors present an analysis of the key interfacial phenomena at the LLZO/Li interface, highlighting recent developments and unresolved issues. Research on the Li7La3Zr2O12 (LLZO)/Li interface is essential for improving the performance of LLZO-based solid-state batteries. In this comment, the authors present an analysis of the key interfacial phenomena at the LLZO/Li interface, highlighting recent developments and unresolved issues.
{"title":"On the interfacial phenomena at the Li7La3Zr2O12 (LLZO)/Li interface","authors":"Kostiantyn V. Kravchyk, Huanyu Zhang, Maksym V. Kovalenko","doi":"10.1038/s42004-024-01350-9","DOIUrl":"10.1038/s42004-024-01350-9","url":null,"abstract":"Research on the Li7La3Zr2O12 (LLZO)/Li interface is essential for improving the performance of LLZO-based solid-state batteries. In this comment, the authors present an analysis of the key interfacial phenomena at the LLZO/Li interface, highlighting recent developments and unresolved issues. Research on the Li7La3Zr2O12 (LLZO)/Li interface is essential for improving the performance of LLZO-based solid-state batteries. In this comment, the authors present an analysis of the key interfacial phenomena at the LLZO/Li interface, highlighting recent developments and unresolved issues.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-4"},"PeriodicalIF":5.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01350-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599031","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 : 2024-11-09DOI: 10.1038/s42004-024-01354-5
Filip Gracias, Radek Pohl, Veronika Sýkorová, Michal Hocek
DNA modifications on pyrimidine nucleobases play diverse roles in biology such as protection of bacteriophage DNA from enzymatic cleavage, however, their role in the regulation of transcription is underexplored. We have designed and synthesized a series of uracil 2ʹ-deoxyribonucleosides and 5ʹ-O-triphosphates (dNTPs) bearing diverse modifications at position 5 of nucleobase, including natural nucleotides occurring in bacteriophages, α-putrescinylthymine, α-glutaminylthymine, 5-dihydroxypentyluracil, and methylated or non-methylated 5-aminomethyluracil, and non-natural 5-sulfanylmethyl- and 5-cyanomethyluracil. The dNTPs bearing basic substituents were moderate to poor substrates for DNA polymerases, but still useful in primer extension synthesis of modified DNA. Together with previously reported epigenetic pyrimidine nucleotides, they were used for the synthesis of diverse DNA templates containing a T7 promoter modified in the sense, antisense or in both strands. A systematic study of the in vitro transcription with T7 RNA polymerase showed a moderate positive effect of most of the uracil modifications in the non-template strand and some either positive or negative influence of modifications in the template strand. The most interesting modification was the non-natural 5-cyanomethyluracil which showed significant positive effect in transcription. DNA modifications on pyrimidine nucleobases play diverse roles in biology such as protection of bacteriophage DNA from enzymatic cleavage, however, their role in the regulation of transcription is underexplored. Here, the authors design and synthesize a series of 5-substituted pyrimidine 2ʹ-deoxyribonucleoside triphosphates and employ them for the synthesis of diverse DNA templates, showing their regulation on in vitro transcription with T7 RNA polymerase.
嘧啶核苷酸上的 DNA 修饰在生物学中发挥着多种作用，如保护噬菌体 DNA 免受酶的裂解，然而，它们在转录调控中的作用还未得到充分探索。我们设计并合成了一系列尿嘧啶 2ʹ-脱氧核苷酸和 5ʹ-O-三磷酸酯（dNTPs），它们在核碱基第 5 位上具有不同的修饰，包括噬菌体中出现的天然核苷酸、α-putrescinylthymine、α-glutaminylthymine、5-dihydroxypentyluracil、甲基化或非甲基化的 5-aminomethyluracil，以及非天然的 5-sulfanylmethyl-和 5-cyanomethyluracil。含有碱性取代基的 dNTPs 是 DNA 聚合酶的中等至低级底物，但在修饰 DNA 的引物延伸合成中仍然有用。它们与之前报道的表观遗传嘧啶核苷酸一起，被用于合成含有在有义、反义或双链上修饰的 T7 启动子的各种 DNA 模板。利用 T7 RNA 聚合酶对体外转录进行的系统研究显示，非模板链上的大多数尿嘧啶修饰都有适度的积极影响，而模板链上的修饰则有一些积极或消极的影响。最有趣的修饰是非天然的 5-氰基甲基尿嘧啶，它对转录有显著的积极影响。嘧啶核碱基上的 DNA 修饰在生物学中发挥着多种作用，如保护噬菌体 DNA 免受酶的裂解，但它们在转录调控中的作用还未得到充分探索。在这里，作者设计并合成了一系列 5-取代的嘧啶 2ʹ-脱氧核苷三磷酸酯，并将它们用于合成不同的 DNA 模板，展示了它们对 T7 RNA 聚合酶体外转录的调控作用。
{"title":"Bacteriophage-related epigenetic natural and non-natural pyrimidine nucleotides and their influence on transcription with T7 RNA polymerase","authors":"Filip Gracias, Radek Pohl, Veronika Sýkorová, Michal Hocek","doi":"10.1038/s42004-024-01354-5","DOIUrl":"10.1038/s42004-024-01354-5","url":null,"abstract":"DNA modifications on pyrimidine nucleobases play diverse roles in biology such as protection of bacteriophage DNA from enzymatic cleavage, however, their role in the regulation of transcription is underexplored. We have designed and synthesized a series of uracil 2ʹ-deoxyribonucleosides and 5ʹ-O-triphosphates (dNTPs) bearing diverse modifications at position 5 of nucleobase, including natural nucleotides occurring in bacteriophages, α-putrescinylthymine, α-glutaminylthymine, 5-dihydroxypentyluracil, and methylated or non-methylated 5-aminomethyluracil, and non-natural 5-sulfanylmethyl- and 5-cyanomethyluracil. The dNTPs bearing basic substituents were moderate to poor substrates for DNA polymerases, but still useful in primer extension synthesis of modified DNA. Together with previously reported epigenetic pyrimidine nucleotides, they were used for the synthesis of diverse DNA templates containing a T7 promoter modified in the sense, antisense or in both strands. A systematic study of the in vitro transcription with T7 RNA polymerase showed a moderate positive effect of most of the uracil modifications in the non-template strand and some either positive or negative influence of modifications in the template strand. The most interesting modification was the non-natural 5-cyanomethyluracil which showed significant positive effect in transcription. DNA modifications on pyrimidine nucleobases play diverse roles in biology such as protection of bacteriophage DNA from enzymatic cleavage, however, their role in the regulation of transcription is underexplored. Here, the authors design and synthesize a series of 5-substituted pyrimidine 2ʹ-deoxyribonucleoside triphosphates and employ them for the synthesis of diverse DNA templates, showing their regulation on in vitro transcription with T7 RNA polymerase.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-11"},"PeriodicalIF":5.9,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01354-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596175","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 : 2024-11-08DOI: 10.1038/s42004-024-01343-8
Udyogi N. K. Conthagamage, Rajitha Rajeshwar T, Stijn van der Ham, Nasim Akhtar, Macallister L. Davis, Senuri G. Jayawardana, Lilia Lopez, Hanumantha Rao Vutukuri, Jeremy C. Smith, Micholas Dean Smith, Víctor García-López
Rotaxanes equipped with actuators hold great potential for developing highly functional molecular machines. Such systems could significantly enhance our ability to study and manipulate biological and artificial membranes. Here, we introduce a rotaxane with a ring featuring two azobenzene photoswitches, which retain their photoreversibility and can be stochastically shuttled along the axle in solution. Studies in model bilayers, supported by molecular dynamics simulations, show how azobenzene photoswitching alters the interaction of rotaxanes with surrounding lipids, leading to changes in lipid packing. Such changes in the lipid bilayer were leveraged to induce the light-triggered release of sulforhodamine B from large unilamellar vesicles. Additionally, light activation of the rotaxanes is shown to induce reversible contraction and expansion of giant unilamellar vesicles. The results provide novel insights into the interactions and operation of rotaxanes in lipid bilayers and their impact on membrane properties. This will aid in developing systems for precise membrane manipulation for applications in biomedicine and bioengineering. Rotaxanes equipped with actuators hold great potential for developing highly functional molecular machines, and could enhance our ability to study and manipulate biological and artificial membranes. Here, the authors introduce a rotaxane with a ring that features two azobenzene photoswitches, and demonstrate that photoswitching can be used to reversibly modulate lipid bilayer structure. This capability was exploited for the light-triggered release of sulforhodamine B from large unilamellar vesicles.
装有致动器的旋转膜具有开发高功能分子机器的巨大潜力。这种系统可以大大提高我们研究和操纵生物膜和人工膜的能力。在这里，我们介绍了一种具有两个偶氮苯光电开关的环状轮烷，它们保持了光可逆性，并能在溶液中沿着轴随机穿梭。在分子动力学模拟支持下对模型双分子层进行的研究表明，偶氮苯光开关如何改变轮烷与周围脂质的相互作用，从而导致脂质堆积的变化。脂质双分子层中的这种变化被用来诱导光触发的磺胺多巴胺 B 从大型单层囊泡中释放出来。此外，光激活轮烷还能诱导巨型单拉米尔小泡的可逆收缩和扩张。这些结果为了解轮烷在脂质双分子层中的相互作用和运作及其对膜特性的影响提供了新的视角。这将有助于开发用于生物医学和生物工程应用的精确膜操纵系统。装有致动器的转轴具有开发高功能分子机器的巨大潜力，可以提高我们研究和操纵生物膜和人工膜的能力。在本文中，作者介绍了一种具有两个偶氮苯光电开关的环状轮烷，并证明光电开关可用于可逆地调节脂质双分子层结构。利用这种能力，光触发了磺胺多巴胺 B 从大型单拉米尔囊泡中的释放。
{"title":"Rotaxanes with a photoresponsive macrocycle modulate the lipid bilayers of large and giant unilamellar vesicles","authors":"Udyogi N. K. Conthagamage, Rajitha Rajeshwar T, Stijn van der Ham, Nasim Akhtar, Macallister L. Davis, Senuri G. Jayawardana, Lilia Lopez, Hanumantha Rao Vutukuri, Jeremy C. Smith, Micholas Dean Smith, Víctor García-López","doi":"10.1038/s42004-024-01343-8","DOIUrl":"10.1038/s42004-024-01343-8","url":null,"abstract":"Rotaxanes equipped with actuators hold great potential for developing highly functional molecular machines. Such systems could significantly enhance our ability to study and manipulate biological and artificial membranes. Here, we introduce a rotaxane with a ring featuring two azobenzene photoswitches, which retain their photoreversibility and can be stochastically shuttled along the axle in solution. Studies in model bilayers, supported by molecular dynamics simulations, show how azobenzene photoswitching alters the interaction of rotaxanes with surrounding lipids, leading to changes in lipid packing. Such changes in the lipid bilayer were leveraged to induce the light-triggered release of sulforhodamine B from large unilamellar vesicles. Additionally, light activation of the rotaxanes is shown to induce reversible contraction and expansion of giant unilamellar vesicles. The results provide novel insights into the interactions and operation of rotaxanes in lipid bilayers and their impact on membrane properties. This will aid in developing systems for precise membrane manipulation for applications in biomedicine and bioengineering. Rotaxanes equipped with actuators hold great potential for developing highly functional molecular machines, and could enhance our ability to study and manipulate biological and artificial membranes. Here, the authors introduce a rotaxane with a ring that features two azobenzene photoswitches, and demonstrate that photoswitching can be used to reversibly modulate lipid bilayer structure. This capability was exploited for the light-triggered release of sulforhodamine B from large unilamellar vesicles.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-11"},"PeriodicalIF":5.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01343-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596116","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 : 2024-11-07DOI: 10.1038/s42004-024-01334-9
Maximilián Lamanec, Svatopluk Civiš, Pavel Hobza
Previously studied complexes with protonic and hydridic hydrogen bonds exhibit significant similarities. The present study provides a detailed investigation of the structure, stabilization, electronic properties, and spectral characteristics of protonic and hydridic hydrogen bonds using low-temperature infrared (IR) spectroscopy and computational methods. Complexes of pentafluorobenzene with ammonia (C₆F₅H⋯NH₃) and triethylgermane with trifluoroiodomethane (Et₃GeH⋯ICF₃) were analyzed using both experimental and computational tools. Additionally, 30 complexes with protonic hydrogen bonds and 30 complexes with hydridic hydrogen bonds were studied computationally. Our findings reveal that, despite the opposite atomic charges on the hydrogens in these hydrogen bonds, and consequently the opposite directions of electron transfer in protonic and hydridic hydrogen bonds, their spectral manifestations - specifically, the red shifts in the X–H stretching frequency and the increase in intensity - are remarkably similar. The study also discusses the limitations of the current IUPAC definition of hydrogen bonding in covering both types of H-bonds and suggests a way to overcome these limitations. Understanding hydrogen-bonding is essential for many fields of natural science. Here, the authors investigate protonic and hydridic hydrogen bonds using low-temperature infrared spectroscopy and computational methods, finding that despite opposite atomic charges on the hydrogens in these hydrogen bonds their spectral manifestations are remarkably similar.
{"title":"On the similar spectral manifestations of protonic and hydridic hydrogen bonds despite their different origin","authors":"Maximilián Lamanec, Svatopluk Civiš, Pavel Hobza","doi":"10.1038/s42004-024-01334-9","DOIUrl":"10.1038/s42004-024-01334-9","url":null,"abstract":"Previously studied complexes with protonic and hydridic hydrogen bonds exhibit significant similarities. The present study provides a detailed investigation of the structure, stabilization, electronic properties, and spectral characteristics of protonic and hydridic hydrogen bonds using low-temperature infrared (IR) spectroscopy and computational methods. Complexes of pentafluorobenzene with ammonia (C₆F₅H⋯NH₃) and triethylgermane with trifluoroiodomethane (Et₃GeH⋯ICF₃) were analyzed using both experimental and computational tools. Additionally, 30 complexes with protonic hydrogen bonds and 30 complexes with hydridic hydrogen bonds were studied computationally. Our findings reveal that, despite the opposite atomic charges on the hydrogens in these hydrogen bonds, and consequently the opposite directions of electron transfer in protonic and hydridic hydrogen bonds, their spectral manifestations - specifically, the red shifts in the X–H stretching frequency and the increase in intensity - are remarkably similar. The study also discusses the limitations of the current IUPAC definition of hydrogen bonding in covering both types of H-bonds and suggests a way to overcome these limitations. Understanding hydrogen-bonding is essential for many fields of natural science. Here, the authors investigate protonic and hydridic hydrogen bonds using low-temperature infrared spectroscopy and computational methods, finding that despite opposite atomic charges on the hydrogens in these hydrogen bonds their spectral manifestations are remarkably similar.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-7"},"PeriodicalIF":5.9,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s42004-024-01334-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596170","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}
The attraction between π-conjugated planar electron donor and acceptor molecules that form many stable charge-transfer (CT) complexes has been explained by quantum chemical CT interactions, although the fundamental origin remains unclear. Here, we demonstrate the mechanism of CT complex formation by potential energy map analysis for TTF–CA and BTBT–TCNQ, using energy decomposition of intermolecular interaction by symmetry-adapted perturbation theory (SAPT) combined with coupled cluster calculation. We find that the source of attraction between donor and acceptor molecules is ascribed primarily to the dispersion force and also to the electrostatic force. In contrast, the contribution of CT interactions to the attractive forces is minimal. We demonstrate that the highly directional feature of the exchange repulsion force, coupled with the attractive dispersion and electrostatic forces, is crucial in determining the intermolecular arrangements of actual CT crystals. These findings are key for understanding the unique structural and electronic properties of π-conjugated CT complexes. The attraction between π-conjugated planar electron donor and acceptor molecules within charge–transfer (CT) complexes has been explained by quantum chemical CT interactions, but its fundamental origins remain unclear. Here, the authors combine symmetry-adapted perturbation theory with coupled cluster calculations to probe the mechanism of CT complex formation in crystals, finding that dispersion and electrostatic forces are dominant, with significant directional exchange repulsion.
{"title":"Origin of the intermolecular forces that produce donor–acceptor stacks in π-conjugated charge-transfer complexes","authors":"Seiji Tsuzuki, Ryota Ono, Satoru Inoue, Satoshi Matsuoka, Tatsuo Hasegawa","doi":"10.1038/s42004-024-01329-6","DOIUrl":"10.1038/s42004-024-01329-6","url":null,"abstract":"The attraction between π-conjugated planar electron donor and acceptor molecules that form many stable charge-transfer (CT) complexes has been explained by quantum chemical CT interactions, although the fundamental origin remains unclear. Here, we demonstrate the mechanism of CT complex formation by potential energy map analysis for TTF–CA and BTBT–TCNQ, using energy decomposition of intermolecular interaction by symmetry-adapted perturbation theory (SAPT) combined with coupled cluster calculation. We find that the source of attraction between donor and acceptor molecules is ascribed primarily to the dispersion force and also to the electrostatic force. In contrast, the contribution of CT interactions to the attractive forces is minimal. We demonstrate that the highly directional feature of the exchange repulsion force, coupled with the attractive dispersion and electrostatic forces, is crucial in determining the intermolecular arrangements of actual CT crystals. These findings are key for understanding the unique structural and electronic properties of π-conjugated CT complexes. The attraction between π-conjugated planar electron donor and acceptor molecules within charge–transfer (CT) complexes has been explained by quantum chemical CT interactions, but its fundamental origins remain unclear. Here, the authors combine symmetry-adapted perturbation theory with coupled cluster calculations to probe the mechanism of CT complex formation in crystals, finding that dispersion and electrostatic forces are dominant, with significant directional exchange repulsion.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-11"},"PeriodicalIF":5.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11542100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590197","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 : 2024-11-05DOI: 10.1038/s42004-024-01337-6
Moritz Stappert, Daniel Kohnhäuser, Tim Seedorf, Janetta Coetzee, Katharina Rox, Hazel L. S. Fuchs, Katarina Cirnski, Christian Leitner, Jennifer Herrmann, Andreas Kirschning, Rolf Müller, Mark Brönstrup
Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D. Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. Here, the authors assess the role of the central D ring pharmacophore in cystobactamids, and develop a potent broad-spectrum antibiotic by exchanging a para-aminobenzoic acid with a terephthalic acid amide.
由于抗菌药耐药性的增加，广谱抗生素的新型支架十分罕见，而且需求量很大。从霉菌中发现的胱内酰胺类药物具有独特的六肽支架，包含五个芳基酰胺，具有强效的抗药性。本研究探讨了胱内酰胺类药物的中心 D 环药理作用，即对氨基苯甲酸（PABA）分子，该分子还被羟基和异丙氧基功能取代。我们改变了这两个含氧取代基，并用生物异构体取代了两个酰胺连接体。我们开发了包括金属介导的芳香族官能化或杂环形成在内的合成路线，最终得到了 19 种新型类似物。所有类似物对 ESKAPE 病原体样本中细菌的抗生素疗效均已确定。虽然羟基和异丙氧基取代基的置换和重新定位没有优势，但用对苯二甲酸酰胺置换 PABA 可得到具有广谱活性、对 AlbD 介导的降解不敏感以及在小鼠体内具有良好药代动力学特性的强效类似物 42。该研究强调了四取代 D 环陡峭的结构-活性关系，以及连接 C 和 D 的酰胺令人惊讶的有利还原。
{"title":"Synthetic studies on the tetrasubstituted D-ring of cystobactamids lead to potent terephthalic acid antibiotics","authors":"Moritz Stappert, Daniel Kohnhäuser, Tim Seedorf, Janetta Coetzee, Katharina Rox, Hazel L. S. Fuchs, Katarina Cirnski, Christian Leitner, Jennifer Herrmann, Andreas Kirschning, Rolf Müller, Mark Brönstrup","doi":"10.1038/s42004-024-01337-6","DOIUrl":"10.1038/s42004-024-01337-6","url":null,"abstract":"Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. The cystobactamids, discovered from myxobacterial sources, have a unique hexapeptidic scaffold with five arylamides and possess potent, resistance-breaking properties. This study investigates the role of the central D-ring pharmacophore in cystobactamids, a para-aminobenzoic acid (PABA) moiety that is additionally substituted by hydroxy and isopropoxy functions. We varied the two oxygenated substituents and replaced both amide connectors with bioisosteres. Synthetic routes were developed that included metal-mediated aromatic functionalization or heterocycle formations, leading to 19 novel analogues. The antibiotic efficacy of all analogues was determined against bacteria from the ESKAPE pathogen panel. While the replacement and the repositioning of hydroxy and isopropoxy substituents was not advantageous, exchanging PABA by terephthalic acid amides led to the highly potent analogue 42 with broad-spectrum activity, insensitivity towards AlbD-mediated degradation and promising pharmacokinetic properties in mice. The study highlights the steep structure-activity relationships in the tetrasubstituted D-ring and a surprisingly favorable reversion of the amide connecting C and D. Novel scaffolds for broad-spectrum antibiotics are rare and in strong demand because of the increase in antimicrobial resistance. Here, the authors assess the role of the central D ring pharmacophore in cystobactamids, and develop a potent broad-spectrum antibiotic by exchanging a para-aminobenzoic acid with a terephthalic acid amide.","PeriodicalId":10529,"journal":{"name":"Communications Chemistry","volume":" ","pages":"1-15"},"PeriodicalIF":5.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11538350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582615","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：