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Computational design of superstable proteins through maximized hydrogen bonding 通过最大化氢键的超稳定蛋白质的计算设计。
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-18 DOI: 10.1038/s41557-025-01998-3
Bin Zheng, Zhuojian Lu, Shangchen Wang, Lichao Liu, Mingjun Ao, Yurui Zhou, Guojing Tang, Ruishi Wang, Yuanhao Liu, Hantian Zhang, Yinying Meng, Jun Qiu, Tianfu Feng, Ziyi Wang, Renming Liu, Yuelong Xiao, Yutong Liu, Ziling Wang, Yifen Huang, Yajun Jiang, Peng Zheng
Hydrogen bonds are fundamental chemical interactions that stabilize protein structures, particularly in β sheets, enabling resistance to mechanical stress and environmental extremes. Here, inspired by natural mechanostable proteins with shearing hydrogen bonds, such as titin and silk fibroin, we de novo designed superstable proteins by maximizing hydrogen-bond networks within force-bearing β strands. Using a computational framework combining artificial intelligence-guided structure and sequence design with all-atom molecular dynamics MD simulations, we systematically expanded protein architecture, increasing the number of backbone hydrogen bonds from 4 to 33. The resulting proteins exhibited unfolding forces exceeding 1,000 pN, about 400% stronger than the natural titin immunoglobulin domain, and retained structural integrity after exposure to 150 °C. This molecular-level stability translated directly to macroscopic properties, as demonstrated by the formation of thermally stable hydrogels. Our work introduces a scalable and efficient computational strategy for engineering robust proteins, offering a generalizable approach for the rational design of resilient protein systems for extreme environments. Nature contains a variety of mechanostable proteins, which all bear extensive hydrogen-bond networks within their β-sheet architectures to sustain high stability under stress. Now through integrating AI-guided design alongside MD simulations and by maximizing hydrogen bonds in β strands, SuperMyo proteins with nanonewton mechanical stability and thermal resilience up to 150 °C were created.
氢键是稳定蛋白质结构的基本化学相互作用,特别是在β片中,使其能够抵抗机械应力和极端环境。在这里,受天然具有剪切氢键的机械稳定蛋白(如titin和丝素蛋白)的启发,我们通过最大化承载力的β链内的氢键网络,重新设计了超稳定蛋白。利用人工智能引导的结构和序列设计与全原子分子动力学MD模拟相结合的计算框架,我们系统地扩展了蛋白质结构,将主氢键的数量从4个增加到33个。所得到的蛋白显示出超过1,000 pN的展开力,比天然titin免疫球蛋白结构域强约400%,并且在暴露于150°C后保持结构完整性。这种分子水平的稳定性直接转化为宏观性质,正如热稳定水凝胶的形成所证明的那样。我们的工作引入了一种可扩展和高效的工程健壮蛋白计算策略,为极端环境下弹性蛋白系统的合理设计提供了一种可推广的方法。
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引用次数: 0
Developing design guidelines for controlling charge transport in DNA. 开发控制DNA电荷传输的设计指南。
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-18 DOI: 10.1038/s41557-025-01999-2
Zahra Aminiranjbar, Caglanaz Akin Gultakti, Amy Zhang, Ersin Emre Oren, Joshua Hihath

Conceptual frameworks that describe the electronic structure of molecules are an integral part of understanding chemical structures and reaction mechanisms and designing organic compounds. Here we develop a preliminary set of design guidelines for controlling the electronic structure of DNA. Recent work indicates that charge delocalization occurs over several bases and results in coherence lengths greater than a single base pair. To examine the interactions between bases and their effects on delocalization, this study investigates the influence of nearest-neighbour base pair interactions on the charge transport properties of DNA duplexes that are predominantly composed of guanine-cytosine base pairs. Results show that, by manipulating the sequence, the conductance can be substantially modified without altering the molecular composition. The electronic density of states are then analysed to deduce a set of design guidelines aimed at maintaining high conductance values in long duplexes. Utilizing these rules, we demonstrate that 20-base-pair DNA sequences can exhibit conductance values surpassing 1 × 10-3G0.

描述分子电子结构的概念框架是理解化学结构和反应机制以及设计有机化合物不可或缺的一部分。在这里,我们开发了一套初步的设计指导方针,以控制DNA的电子结构。最近的研究表明,电荷离域发生在多个碱基上,导致相干长度大于单个碱基对。为了研究碱基之间的相互作用及其对离域的影响,本研究研究了最近邻碱基对相互作用对主要由鸟嘌呤-胞嘧啶碱基对组成的DNA双链的电荷传输特性的影响。结果表明,通过控制序列,可以在不改变分子组成的情况下大幅度改变电导。然后分析状态的电子密度,以推导出一套设计准则,旨在保持长双工的高电导值。利用这些规则,我们证明了20碱基对DNA序列可以显示超过1 × 10-3G0的电导值。
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引用次数: 0
Dearomative syn-1,4-hydroalkylation and C(sp2)−H alkylation of arenes controlled by chemoselective electrolysis 化学选择性电解控制芳烃的脱芳syn-1,4-氢烷基化和C(sp2)-H烷基化。
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-17 DOI: 10.1038/s41557-025-02001-9
Chao Wan, Chao Yang, Magnus Rueping, Chen Zhu, Lin Guo, Wujiong Xia
Dearomative functionalization of arenes represents a powerful synthetic strategy for the rapid assembly of complex chemical architectures. A significant challenge in this process is overcoming the inherent aromaticity of arenes. Here, leveraging the potential of organic electrolysis, we show the development of a dearomative syn-1,4-hydroalkylation reaction targeting electron-deficient arenes and heteroarenes. This electrochemical approach, conducted under mild, operationally straightforward and scalable conditions, facilitates the synthesis of alkylated syn-1,4-cyclohexadienes with high chemoselectivity, regioselectivity and stereoselectivity. In addition, this alkylation protocol is controllable and switchable. By employing a niobium plate as the anode and nBu4NBr as the supporting electrolyte, our method enables the para-selective C(sp2)–H alkylation of (hetero)arenes via electrolysis. Both reactions exhibit broad substrate scope and demonstrate excellent compatibility with various electron-deficient arenes and alkyl bromides. Furthermore, preliminary mechanistic studies and density functional theory calculations have been performed to elucidate the reaction mechanism and to rationalize the observed chemoselectivity, regioselectivity and stereoselectivity. Dearomative functionalization is an extraordinary approach for transforming inert, two-dimensional arenes into three-dimensional architectures. Now it has been shown that electrolysis could facilitate dearomative syn-1,4-hydroalkylation and para-selective C(sp2)–H alkylation of electron-deficient (hetero)arenes. Mechanistic studies indicate that the chemoselectivity is primarily governed by the choice of supporting electrolyte and electrode.
芳烃的脱芳功能化为复杂化学结构的快速组装提供了一种强有力的合成策略。这一过程的一个重大挑战是克服芳烃固有的芳香性。在这里,利用有机电解的潜力,我们展示了一个针对缺电子芳烃和杂芳烃的去芳香syn-1,4-氢烷基化反应的发展。这种电化学方法在温和、操作简单和可扩展的条件下进行,有助于合成具有高化学选择性、区域选择性和立体选择性的烷基化syn1,4 -环己二烯。此外,这种烷基化协议是可控的和可切换的。该方法采用铌板为阳极,nBu4NBr为支撑电解质,实现了(杂)芳烃的电解合选C(sp2)-H烷基化反应。这两种反应都表现出广泛的底物范围,并与各种缺电子芳烃和烷基溴具有良好的相容性。此外,还进行了初步的机理研究和密度泛函理论计算,阐明了反应机理,并对所观察到的化学选择性、区域选择性和立体选择性进行了理顺。
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引用次数: 0
Tetrafunctional cyclobutanes tune toughness via network strand continuity 四功能环丁烷通过网络链的连续性调节韧性
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-14 DOI: 10.1038/s41557-025-01984-9
Abraham Herzog-Arbeitman, Ilia Kevlishvili, Devosmita Sen, Julianna Lian, Joshika Chakraverty, Peter Mueller, Shu Wang, Bradley D. Olsen, Heather J. Kulik, Stephen L. Craig, Jeremiah A. Johnson
Customizing the toughness of polymer networks independently of their chemical composition and topology remains an unsolved challenge. Traditionally, polymer network toughening is achieved by using specialized monomers or solvents or adding secondary networks/fillers that substantially alter the composition and may limit applications. Here we report a class of force-responsive molecules—tetrafunctional cyclobutanes (TCBs)—that enable the synthesis of single-network end-linked gels with substantially decreased or increased toughness, including unusually high toughness for dilute end-linked gels, with no other changes to network composition. This behaviour arises from stress-selective force-coupled TCB reactivity when stress is imparted from multiple directions simultaneously, which traditional bifunctional mechanophores cannot access. This molecular-scale mechanoreactivity translates to bulk toughness through a topological descriptor, network strand continuity, that describes the effect of TCB reactivity on the consequent local network topology. TCB mechanophores and the corresponding concepts of stress-selective force-coupled reactivity and strand continuity offer design principles for tuning the toughness of simple yet commonly used single-network gels. Toughness and stiffness in polymer gels are generally coupled to the network structure and composition. Now it has been shown that stress-selective mechanophore junctions—tetrafunctional cyclobutanes (TCBs)—with minor structural modifications can tune these properties independently in end-linked gels. TCBs increase or decrease toughness by remodelling network topology at the crack tip.
定制不依赖于其化学成分和拓扑结构的聚合物网络的韧性仍然是一个未解决的挑战。传统上,聚合物网络增韧是通过使用专门的单体或溶剂或添加二次网络/填料来实现的,这实质上改变了聚合物的组成,并可能限制应用。在这里,我们报告了一类力响应分子-四功能环丁烷(TCBs) -能够合成单网端连接凝胶,其韧性显著降低或增加,包括稀释端连接凝胶的异常高韧性,而网络组成没有其他变化。当从多个方向同时施加应力时,这种行为源于应力选择力耦合TCB反应性,这是传统的双功能机械载体无法达到的。这种分子尺度的机械反应性通过拓扑描述符转化为整体韧性,网络链连续性描述了TCB反应性对随后的局部网络拓扑结构的影响。TCB机械载体和相应的应力选择力耦合反应性和链连续性概念为调整简单但常用的单网凝胶的韧性提供了设计原则。聚合物凝胶的韧性和刚度通常与网络结构和组成有关。现在已经证明,应力选择性机械基团连接-四功能环丁烷(TCBs) -通过轻微的结构修饰可以在端链凝胶中独立调节这些特性。tcb通过重塑裂纹尖端的网络拓扑结构来增加或降低韧性。
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引用次数: 0
Metal-hydroxyls mediate intramolecular proton transfer in heterogeneous O–O bond formation 金属羟基介导非均相O-O键形成中的分子内质子转移
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-14 DOI: 10.1038/s41557-025-01993-8
Hao Yang, Fusheng Li, Shaoqi Zhan, Yawen Liu, Tianqi Liu, Linqin Wang, Wenlong Li, Mårten S. G. Ahlquist, Sumbal Farid, Rile Ge, Junhu Wang, Marc T. M. Koper, Licheng Sun
Metal (hydro)oxides are among the most effective heterogeneous water oxidation catalysts. Elucidating the interactions between oxygen-bridged metal sites at a molecular level is essential for developing high-performing electrocatalysts. Here we demonstrate that adjacent metal-hydroxyl groups function as intramolecular proton–electron transfer relays to enhance water oxidation kinetics. We achieved this using a well-defined molecular platform with an aza-fused π-conjugated microporous polymer that coordinates molecular Ni or Ni–Fe sites that emulate the structure of the most active edge sites in Ni–Fe materials for studying the heterogeneous water oxidation mechanism. We combine experimental and computational results to reveal the origin of pH-dependent reaction kinetics for O–O bond formation. We find both the anions in solution and the adjacent Ni3+–OH site act as proton transfer relays, facilitating O–O bond formation and leading to pH-dependent water oxidation kinetics. This study provides significant insights into the critical role of electrolyte pH in water oxidation electrocatalysis and enhancement of water oxidation activity in Ni–Fe systems. Intramolecular proton relays are proposed to enhance oxygen evolution for heterogeneous (hydro)oxide electrocatalysts, but molecular-level evidence remains limited. Now it has been shown, using an aza-fused microporous polymer with Ni–Fe sites, that adjacent Ni3+–OH sites relay protons from Fe⁴⁺=O, accelerating the water nucleophilic attack pathway and achieving high turnover frequencies with pH-tunable kinetics.
金属(氢)氧化物是最有效的非均相水氧化催化剂之一。在分子水平上阐明氧桥金属位之间的相互作用对于开发高性能电催化剂至关重要。在这里,我们证明了相邻的金属羟基作为分子内质子-电子转移的继电器,以增强水的氧化动力学。我们利用一个定义良好的分子平台,利用偶氮融合的π共轭微孔聚合物来协调分子Ni或Ni - fe位点,模拟Ni - fe材料中最活跃的边缘位点的结构,以研究非均相水氧化机制。我们将实验和计算结果结合起来,揭示了O-O键形成的ph依赖反应动力学的起源。我们发现溶液中的阴离子和邻近的Ni 3+ -OH位点都充当质子转移继电器,促进O-O键的形成,并导致ph依赖的水氧化动力学。本研究对电解质pH在Ni-Fe体系中水氧化电催化和水氧化活性增强中的关键作用提供了重要的见解。
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引用次数: 0
Construction of sulfur stereocentres by asymmetric geminate recasting 不对称双晶重铸法制备硫立体中心
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-14 DOI: 10.1038/s41557-025-01996-5
Arka Porey, Ramon Trevino, Sachchida Nand, Seth O. Fremin, Shree Krishna Dhakal, Babu Raj Dhungana, Arko Das, Vy T. B. Nguyen, William T. Thompson, Dylan P. Moran, Chandan Kumar Giri, Hadi D. Arman, Daniel J. Wherritt, Oleg V. Larionov
Radical pairs generated by light-induced or heat-induced bond cleavage play a central role in biochemical transformations and the synthesis of pharmaceuticals, polymers and industrial chemicals. When such cleavage occurs at a stereocentre in chiral molecules, recombination of the produced radicals can lead to either enantiomer, typically resulting in racemization. Achieving selective conversion of racemic mixtures into single enantiomers is highly desirable yet challenging due to the uncontrolled behaviour of free radicals. Here we show that stereocontrol over these reactions can be achieved through asymmetric geminate recasting: a process in which homolysis and recombination occur within a solvent cage under the influence of a chiral photocatalyst. This strategy enabled the selective construction of chiral sulfur stereocentres via deracemization of sulfinamides, providing access to valuable sulfur-containing building blocks. The approach opens unexplored possibilities for controlling stereochemistry in radical reactions and may inspire broader applications in asymmetric synthesis, medicinal chemistry and materials development. Controlling the stereoselectivity of radical reactions remains a major challenge due to the high reactivity of free radicals. Now it has been shown that asymmetric geminate recasting—a catalytic process in which radicals recombine after bond cleavage—can be used to produce chiral sulfur centres through photocatalytic deracemization of sulfinamides.
由光诱导或热诱导的键裂解产生的自由基对在生化转化和药物、聚合物和工业化学品的合成中起着核心作用。当这种切割发生在手性分子的立体中心时,所产生的自由基的重组可以导致任何一种对映体,通常导致外消旋。实现选择性地将外消旋混合物转化为单个对映体是非常理想的,但由于自由基的不受控制的行为具有挑战性。在这里,我们展示了对这些反应的立体控制可以通过不对称孪晶重铸来实现:在手性光催化剂的影响下,在溶剂笼中均解和重组发生的过程。这种策略使得通过亚胺的离消酰基化选择性地构建手性硫立体中心成为可能,从而提供了获得有价值的含硫构建块的途径。该方法为控制自由基反应中的立体化学开辟了未知的可能性,并可能在不对称合成、药物化学和材料开发方面激发更广泛的应用。由于自由基的高反应活性,控制自由基反应的立体选择性仍然是一个主要的挑战。目前已有研究表明,不对称孪晶重铸——一种在键断裂后自由基重新结合的催化过程——可以通过光催化亚胺的去离中心反应产生手性硫中心。
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引用次数: 0
Transient Au–Cl adlayers modulate the surface chemistry of gold nanoparticles during redox reactions 在氧化还原反应过程中,瞬态Au-Cl层调节金纳米颗粒的表面化学性质
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-13 DOI: 10.1038/s41557-025-01989-4
Sarah May Sibug-Torres, Marika Niihori, Elle Wyatt, Rakesh Arul, Nicolas Spiesshofer, Tabitha Jones, Duncan Graham, Bart de Nijs, Oren A. Scherman, Reshma R. Rao, Mary P. Ryan, Alexander Squires, Christopher N. Savory, David O. Scanlon, Abdalghani Daaoub, Sara Sangtarash, Hatef Sadeghi, Jeremy J. Baumberg
Controlling surface chemistry at the nanoscale is essential for stabilizing structure and tuning function in plasmonic, catalytic and sensing systems, where even trace ligands or ions can reshape surface charge and reactivity. However, probing such dynamic interfaces under operando conditions remains challenging, limiting efforts to engineer nanomaterials with precision. Here, using in situ surface-enhanced Raman spectroscopy, we identify a transient Au–Cl adlayer that forms during electrochemical cycling at gold interfaces. The adlayer exhibits significant charge transfer between gold and chlorine, generating an outward-facing dipole that polarizes neighbouring atoms and modulates the local potential. This dipole stabilizes nanogap interfaces and directs oriented ligand rebinding, enabling reversible reconstruction of subnanometre architectures. It also alters interfacial charge distributions and mediates electron transfer between gold oxidation states, acting as a redox-active intermediate. These findings show how transient surface species shape nanoscale reactivity and stability, offering strategies for designing catalysts, sensors and nanomaterials. Controlling nanoscale interfaces is key for ensuring stable plasmonic and catalytic function yet remains difficult to achieve under operando conditions. Now it has been shown that transient Au–Cl adlayers function as redox-active Au(I) intermediates, modulating interfacial electrostatics. This modulation stabilizes gold nanogaps and directs ligand rebinding, thereby enabling reproducible regeneration of subnanometre architectures.
在纳米尺度上控制表面化学对于稳定等离子体、催化和传感系统的结构和调节功能至关重要,在这些系统中,即使是微量配体或离子也可以重塑表面电荷和反应性。然而,在操作条件下探测这种动态界面仍然具有挑战性,限制了精确设计纳米材料的努力。在这里,使用原位表面增强拉曼光谱,我们确定了在金界面电化学循环过程中形成的瞬态Au-Cl层。该层在金和氯之间表现出明显的电荷转移,产生一个向外的偶极子,使邻近原子极化并调节局部电位。这种偶极子稳定了纳米间隙界面和定向配体再结合,使亚纳米结构的可逆重建成为可能。它还可以改变界面电荷分布,并在金氧化态之间介导电子转移,作为氧化还原活性中间体。这些发现揭示了瞬态表面物质如何影响纳米级反应性和稳定性,为设计催化剂、传感器和纳米材料提供了策略。
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引用次数: 0
Stereodivergent construction of non-adjacent stereocentres via migratory functionalization of alkenes 通过烯烃迁移官能化的非相邻立体中心的立体发散构造
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-12 DOI: 10.1038/s41557-025-01994-7
Guodong Ju, Xueyuan Yan, Haohao Bai, Mengyuan Liu, Xinping Xi, Yi Liu, Genping Huang, Chao Wang
Stereodivergent construction of multiple stereocentres is one of the most essential tasks in asymmetric synthesis. However, strategies for assembling all possible stereoisomers of optically active compounds bearing non-adjacent stereocentres remain scarce and suffer from certain limitations in terms of reaction types and chemical space. Here we succeed in utilizing the chain walking strategy to realize the simultaneous construction of acyclic 1,n-non-adjacent (n = 3 or 4) stereocentres via Ni-catalysed migratory hydroalkylation of trisubstituted alkenes in an enantioselective and diastereodivergent manner. A series of alkyl units can be site-selectively installed at α-C(sp3)–H sites adjacent to nitrogen, affording chiral amines bearing an α-stereogenic centre and a remote (γ- or δ-) all-alkyl-substituted stereocentre. All four stereoisomers can be accessed using a single catalyst via an appropriate selection of the olefin geometry and ligand configuration, with exceptional control of stereochemistry. This simple and mild platform offers opportunities for the streamlined synthesis of complex bioactive molecules and medicinally relevant scaffolds. Stereodivergent construction of non-adjacent stereocentres remains challenging in asymmetric synthesis, with prior examples limited to one cyclic or allenic stereocentre. Now it has been shown that Ni-catalysed migratory hydroalkylation of trisubstituted alkenes enables enantio- and diastereodivergent access to all four stereoisomers of acyclic molecules bearing remote 1,3- or 1,4-stereocentres.
多立体中心的立体发散构造是不对称合成中最重要的任务之一。然而,组装具有非相邻立体中心的所有可能的光学活性化合物的立体异构体的策略仍然很少,并且在反应类型和化学空间方面受到一定的限制。在这里,我们成功地利用链行走策略,通过镍催化的三取代烯烃以对映选择性和非对映发散的方式迁移氢烷基化,实现了无环1,n-非相邻(n = 3或4)立体中心的同时构建。一系列烷基单元可以选择性地安装在靠近氮的α-C(sp3) - h位点上,形成具有α-立体中心和远端(γ-或δ-)全烷基取代立体中心的手性胺。所有四种立体异构体都可以使用单一催化剂,通过适当选择烯烃的几何形状和配体构型,并具有良好的立体化学控制。这个简单而温和的平台为复杂生物活性分子和医学相关支架的流线型合成提供了机会。非相邻立体中心的立体发散构造在不对称合成中仍然具有挑战性,先前的例子仅限于一个环或异位体中心。现在已经证明,镍催化的三取代烯烃的迁移氢烷基化使得对映体和非对映体能够接触到具有远端1,3或1,4立体中心的非环分子的所有四种立体异构体。
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引用次数: 0
Compact RNA sensors for increasingly complex functions of multiple inputs 紧凑型RNA传感器用于日益复杂的多输入功能。
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-12 DOI: 10.1038/s41557-025-01907-8
Christian A. Choe, Johan O. L. Andreasson, Feriel Melaine, Wipapat Kladwang, Michelle J. Wu, Fernando Portela, Roger Wellington-Oguri, John J. Nicol, Hannah K. Wayment-Steele, Michael Gotrik, Eterna Participants, Purvesh Khatri, William J. Greenleaf, Rhiju Das
Designing single molecules that compute general functions of input molecular partners is a major unsolved challenge in molecular design. Here we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from the online game Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm, Nucleologic, that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results expand the possibilities for using compact, single-molecule sensors in a range of applications previously constrained by design complexity. Designing single molecules capable of complex sensing functions is challenging. Now, using crowdsourced RNA designs from the online game Eterna, compact single-molecule sensors have been demonstrated for a variety of tasks, including a complex three-input tuberculosis diagnostic. The development of a Monte Carlo Tree Search algorithm enabled automated design of similarly sophisticated nucleic-acid sensors.
设计计算输入分子伙伴的一般函数的单分子是分子设计中尚未解决的主要挑战。在这里,我们证明了对来自在线游戏Eterna的各种RNA设计的高通量,迭代实验测试产生了输入寡核苷酸浓度功能日益复杂的传感器。在设计了激活比超过检测极限的单输入RNA传感器后,我们创建了逻辑门,包括具有挑战性的异或门和异或门,以及响应两个输入比的传感器。最后,我们描述了OpenTB挑战,它引发了85个核苷酸传感器,根据三个基因片段的产物比例计算诊断活动性结核病的分数。在OpenTB设计策略的基础上,我们创建了一个算法,Nucleologic,它产生了类似的紧凑型传感器,用于基于RNA和DNA的三个基因评分。这些结果扩大了在一系列应用中使用紧凑的单分子传感器的可能性,这些应用以前受到设计复杂性的限制。
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引用次数: 0
Triply convergent Ni-electrocatalytic assembly of 1,1-diaryl cyclobutanes, azetidines and oxetanes 1,1-二芳基环丁烷、氮杂丁烷和氧烷的三收敛镍电催化组装
IF 20.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-11-11 DOI: 10.1038/s41557-025-01990-x
Luca Massaro, Philipp Neigenfind, Andrew Feng, Gannon Kuehn, Flynn C. Attard, Ava DeSanti, Michael R. Collins, Martin Bravo, Raymond K. Twumasi, Doris Chen, Philippe N. Bolduc, Michael Nicastri, Megan A. Emmanuel, Martins S. Oderinde, Maximilian D. Palkowitz, Xiaofan Zheng, Arianne C. Hunter, Kaid C. Harper, Chet C. Tyrol, Pavel K. Mykhailiuk, Yu Kawamata, Phil S. Baran
The pursuit of increasingly complex, three-dimensional molecules is pushing the boundaries of modern organic synthesis, particularly in drug discovery where rigid, saturated scaffolds such as cyclobutanes, azetidines and oxetanes are in high demand. Here we outline a modular, scalable, chemoselective approach to solve this problem using simple α-bromoacids and aryl halides as intuitive starting materials. As demonstrated herein, a sequential series of nickel-electrocatalytic cross-couplings can be enlisted to enable rapid access to such structures, many of which have been nearly impossible to access before without recourse to time-consuming polar bond disconnections that are inherently limiting in terms of accessible chemical space. The scalability of this new reaction sequence is demonstrated, alongside direct applications to known patented structures. A simple user guide is also presented to accelerate adoption of this strategy in medicinal chemistry and related fields. Molecular scaffolds bearing 1,1-diaryl-substituted four-membered rings remain difficult to access using traditional synthesis. Now it has been shown that a modular, nickel-electrocatalytic sequence enables the programmable, scalable and chemoselective synthesis of these high-value motifs, offering broad utility across drug discovery and showcasing strategic applications to patented intermediates.
对越来越复杂的三维分子的追求正在推动现代有机合成的边界,特别是在药物发现方面,对环丁烷、氮杂啶和氧烷等刚性饱和支架的需求量很大。在这里,我们概述了一个模块化的、可扩展的、化学选择性的方法来解决这个问题,使用简单的α-溴酸和芳基卤化物作为直观的起始材料。正如本文所展示的,一系列连续的镍电催化交叉偶联可以使快速访问这些结构成为可能,其中许多结构以前几乎不可能访问,除非诉诸耗时的极性键断开,这些极性键断开本质上限制了可访问的化学空间。这种新的反应序列的可扩展性被证明,以及直接应用于已知的专利结构。为加快该策略在药物化学及相关领域的应用,还提供了一个简单的使用指南。含有1,1-二芳基取代四元环的分子支架仍然难以用传统的合成方法获得。现在已经证明,模块化的镍电催化序列使这些高价值基序的可编程,可扩展和化学选择性合成成为可能,为药物发现提供了广泛的实用性,并展示了专利中间体的战略应用。
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Nature chemistry
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