Accounts of Chemical Research最新文献

{"title":"Precision Protein Modification via Ligation and Bioconjugation at Selenocysteine","authors":"Max J. Bedding,&nbsp;Sameer S. Kulkarni,&nbsp;Richard J. Payne","doi":"10.1021/acs.accounts.6c00543","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00543","url":null,"abstract":"<p>Selenocysteine (Sec), oftenreferred to as the21st amino acid,is a rare yet essential amino acid found in a small number of naturallyoccurring selenoproteins that play critical roles in redox regulation,antioxidant defence, and hormone metabolism. Owing to its distinctchemical properties, namely enhanced nucleophilicity, lower reductionpotential, and versatile redox behaviour of the side chain selenol/diselenidemoiety relative to the thiol/disulfide of Cys, Sec has recently beenleveraged for a range of applications in protein science.</p><p>Inthis account, we summarize our endeavors towards the developmentof selenium-mediated ligation methodologies for the rapid and highlyefficient assembly of proteins, including those bearing native post-translationalmodifications (PTMs) or “designer” modifications. Keyinnovations include the diselenide–selenoester ligation (DSL)and expressed protein selenoester ligation (EPSL). DSL enables therapid fusion of unprotected peptides through a chemoselective reactionbetween peptide selenoesters and selenopeptides. Notably, in the presenceof suitable additives, DSL can be performed at nanomolar concentrations,providing access to challenging classes of modified proteins, suchas lipoproteins, that are difficult to access via other techniques.We also discuss the extension of DSL chemistry to larger proteinsthrough the generation of protein selenoesters from recombinantlyexpressed intein fusion proteins. By combining the advantages of recombinantbacterial expression and the rapid kinetics of DSL at Sec, we highlightthe use of the EPSL technology for the generation of large, aggregation-proneproteins, including the lipidated GTPase YPT6 and mycobacterial lipoproteinsas novel vaccine antigens. Beyond protein synthesis and semi-synthesis,we have also demonstrated the utility of selenocysteine (Sec) as apowerful bioconjugation handle. Specifically, we highlight two novelSec-selective bioconjugation reaction manifolds in this account; thephotocatalytic diselenide contraction (PDC) and electrochemical selenoetherification(e-SE). These transformations enable dimerization and site-specificfunctionalization of peptide and protein diselenides with exceptionalregio- and chemoselectivity, offering significant advantages overother bioconjugation methods.</p><p>Overall, we believe that thesetechnologies represent a major advancein the generation of site-selectively modified peptides and proteins,unlocking new possibilities for applications in fundamental biologybut also the generation of next-generation diagnostics and therapeuticsbearing precise modifications at defined sites on proteins.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3450–3462"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-Scale Supply–Demand Matching of Reactive Species in Electrocatalytic Reduction Reactions","authors":"Huai Qin Fu,&nbsp;Peng Fei Liu,&nbsp;Porun Liu,&nbsp;Hua Gui Yang,&nbsp;Huijun Zhao","doi":"10.1021/acs.accounts.6c00559","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00559","url":null,"abstract":"&lt;p&gt;Electrocatalytic reduction reactions,such as the hydrogen evolutionreaction (HER) and the carbon dioxide, carbon monoxide, and nitrogenelectroreduction reactions (CO&lt;sub&gt;2&lt;/sub&gt;RR, CORR, NRR), providepromising and sustainable routes for energy conversion, carbon utilization,and low-emission chemical manufacturing. Despite significant advancesin catalyst development, the practical implementation of these reactions,particularly under high-current-density conditions, remains severelyconstrained by inefficiencies in activity, selectivity, and stability.The electrocatalyst performance has traditionally been interpretedand optimized largely in terms of intrinsic activity descriptors,such as adsorption free energies of reaction intermediates, electronic-statecharacteristics of active sites, and related electronic-structureparameters, including the d-band center and density of states. Thesedescriptors are typically evaluated in modeling under the implicitassumption that reactive species are continuously and sufficientlysupplied to catalytic active sites. Under practical operating conditions,especially at high reaction fluxes, however, this assumption is oftenno longer valid. A critical limitation arises from the mismatch betweenthe supply capacity of reactive species (e.g., *H, lattice O, andCO&lt;sub&gt;2&lt;/sub&gt;) and the demand strength imposed by active sites. Athigh current densities, electrochemical interfaces operate far fromequilibrium, such that reaction performance is no longer governedsolely by the intrinsic catalytic activity of a single active sitebut also by the rates of generation, replenishment, transfer, andutilization of elementary reaction species. Such supply–demandimbalances can reduce overall reaction rates and alter reaction pathways.However, the role of species supply–demand matching acrossdifferent scales has rarely been systematically incorporated intoreaction mechanisms or catalyst design strategies.&lt;/p&gt;&lt;p&gt;In this Account,we propose a reactive species cross-scale supply–demandmatching framework in electroreduction reactions across atomic, nanoscale,and macroscale regimes. We demonstrate that catalytic performanceis governed not only by intrinsic activity but also by whether theavailability of reactive species becomes insufficient, excessive,or appropriately matched to the demand of active sites. At the nanoscale,we uncover hydrogen spillover as an interfacial mechanism that couples*H generation and consumption sites, enabling *H supply–demandbalance in alkaline HER. At the atomic scale, extending this conceptto proton-coupled electron transfer reactions reveals that efficienthydrogen transfer is governed by spatial proximity, requiring angstrom-scalesite separation. Furthermore, we identify lattice oxygen as an alternativeatomic-scale supply pathway in CO&lt;sub&gt;2&lt;/sub&gt;RR and provide directexperimental evidence for lattice oxygen participation. At the macroscale,we develop quantitative CO&lt;sub&gt;2&lt;/sub&gt; supply–demand matchingmodels that co","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3437–3449"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemically Induced Proximity for Targeted Protein O-GlcNAcylation","authors":"Bowen Ma,&nbsp;Tongyang Xu,&nbsp;Zhihao Guo,&nbsp;Billy Wai-Lung Ng","doi":"10.1021/acs.accounts.6c00453","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00453","url":null,"abstract":"<p><em>O-</em>GlcNAcylationis a ubiquitous post-translationalmodification across the mammalian proteome, yet determining how individual <em>O-</em>GlcNAcylation events control specific protein functionsremains a central challenge. The <em>O-</em>GlcNAc cycle isgoverned by two enzymes: <em>O-</em>GlcNAc transferase (OGT),which installs <em>O-</em>GlcNAc, and <em>O-</em>GlcNAcase(OGA), which removes it. Because these enzymes act on thousands ofproteins, conventional methods, such as pharmacological inhibitionof OGT or OGA, produce broad cellular effects that are difficult toassign to individual substrates. This gap has motivated the developmentof targeted <em>O-</em>GlcNAcylation strategies, includinggenetically encoded and chemical biology tools, which have shown that <em>O-</em>GlcNAc can be selectively installed on defined proteinsto interrogate protein-specific <em>O-</em>GlcNAc functions.</p><p>This Account describes the development of <em>O-</em>GlcNAcTArgeting Chimeras, or OGTACs, as chemical tools for targeted <em>O-</em>GlcNAc installation. OGTACs are bifunctional moleculesthat can recruit OGT to a specific protein of interest. Specifically,an OGTAC consists of an OGT-engaging element, a linker, and a target-recognitionmotif, which together bring OGT into proximity with a selected substrate.</p><p>Our studies show that chemically induced proximity can redirectOGT toward selected proteins, thereby creating targeted <em>O-</em>GlcNAc writing that can partially bypass TPR-domain-mediated substraterecognition under engineered recruitment conditions. A central lessonis that productive <em>O-</em>GlcNAc writing requires notonly recruitment, but also proper ternary-complex formation and noninhibitoryOGT engagement. Moreover, the target-recognition motif determinesthe targetable protein space and achievable selectivity of the platform.By linking local <em>O-</em>GlcNAc installation to changesin protein turnover, signaling, and transcriptional output, OGTACsprovide a conceptual framework for using induced proximity to modulateprotein functions.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3336–3346"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing Sustainable Chemistry with AI","authors":"Jiyizhe Zhang,&nbsp;Polina Yaseneva,&nbsp;Alexei Lapkin","doi":"10.1021/acs.accounts.6c00552","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00552","url":null,"abstract":"&lt;p&gt;Today we are experiencing anunprecedentedly rapid transformationof science, driven by advances in computing and artificial intelligence(AI). At the same time, there are growing cumulative pressures ofclimate change impacts that not only affect economies but are creatingsignificant societal challenges. The confluence of technology pushand environmental–socioeconomic pressures is promoting thedevelopment of sustainable chemistry. The link between the transitionto sustainability in chemistry and the digital transformation of R&amp;Dand manufacturing has been the long-standing focus in our research(Fantke, P.; et al. &lt;em&gt;Chem&lt;/em&gt; &lt;strong&gt;2021&lt;/strong&gt;, &lt;em&gt;7&lt;/em&gt;, 2866 doi: 10.1016/j.chempr.2021.09.012). Sustainabilityis not a feature of a single chemical product or a process. It isincorrect to talk about “sustainable polyethylene”,as such narrow framing will miss many issues in the more holisticsystem that not only includes the cradle-to-grave life cycle emissionimpacts of polyethylene but also considers all aspects of equity,impact on biodiversity, resilience of supply chains, etc. Sustainablechemistry makes sense only as a complex system. An analysis of complexsystems requires large amounts of data and the use of appropriateanalytical tools, such as advanced machine learning techniques.&lt;/p&gt;&lt;p&gt;The chemical industry has been an early adopter of digital technologies,motivated by the inherent complexity of chemical systems and the needfor efficiency to stay economically competitive. As early as the 1970s,cheminformatics tools were introduced to support structure–propertyanalysis. In the 1980s, we saw the broad adoption of process modelingand simulation tools for design, scale-up, and optimization of chemicalprocesses, paralleled with developments in the field of process systemengineering and control. Today’s digital transition is muchdeeper; everything from scientific discovery (molecules, materials,and phenomena) to chemical process development, analytical methodsand process analytical technologies, and plant operation is beingreshaped. This deep transformation includes the development of a radicallydifferent approach to data in chemistry. Advances in self-drivinglaboratories, agentic AI workflows, and digital factories requireaccess to structured, semantically rich data.&lt;/p&gt;&lt;p&gt;In this Account,we focus on three key areas of digitalizationand AI technologies advancing chemistry and chemical process developmenttoward net-zero targets. First, we discuss how data mining tools areused to analyze the existing value chains and identify opportunitiesto integrate net-zero feedstocks. When new molecules are introduced,data-driven route planning can be employed to design alternative syntheticpathways, which then need to be rigorously evaluated. Second, we focuson how to use AI to accelerate discoveries in chemistry, includingthe innovative design of catalysts, rational selection of solvents,and identification of optimal reaction conditions. By leveraging st","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3426–3436"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149219022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Direct to Alternating Current Electrosynthesis: Transition-Metal-Catalyzed Oxidative Cross-Coupling with Hydrogen Evolution","authors":"Qinghong Yang,&nbsp;Zhengze Wu,&nbsp;Yi Zhao,&nbsp;Bufan Dang,&nbsp;Li Zeng,&nbsp;Aiwen Lei","doi":"10.1021/acs.accounts.6c00562","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00562","url":null,"abstract":"<p>Electrochemical transition-metalcatalysis is an effective yetunderexplored platform for molecular construction. Combining the advantagesof electrochemically driven oxidation processes with the selectivitycontrol afforded by transition-metal catalysis, this field is characterizedby a rich variety of reaction types, mild conditions, and high controllability.However, it has long faced major scientific challenges: there is amismatch between electron transfer on the electrode surface and therate of catalyst-mediated reactant activation in solution, which complicatesprecise control over reaction selectivity, and metal catalysts (especiallyPd, Ag, and Cu) are prone to reductive deactivation, leading to prematuretermination of the reactions. To address these challenges, our grouphas developed three main strategies using oxidative cross-couplingreactions as a representative. First, in direct current (DC) electrosynthesis,we employed a divided cell to prevent the metal catalyst from migratingto the cathode. Second, under specific ligand and solvent combinations,we realized electro-oxidative metal-catalyzed reactions in an undividedcell by precisely controlling the redox potential. To this end, thesubstrates were equipped with directing groups (DGs) capable of chelatingwith the metal cation or an extra ligand was introduced into the reactionsystem, both of which effectively suppressed reductive deactivation.Through this approach, we successfully achieved a series of Pd-, Co-,and Mn-catalyzed oxidative C–H functionalization reactions.Third, we developed an unsymmetrical alternating current (AC)-drivenmetal catalysis strategy designed to accommodate a broader range ofreaction patterns. By precisely adjusting the duty ratio and currentof the AC waveform, we ensured smooth reactivation of the metal catalyst.This programmed waveform further enabled the maintenance of a highconcentration of the active metal species through a dynamic balance.Consequently, we successfully achieved Cu-, Ag-, and Pd-catalyzedoxidative C–H cross-coupling reactions. The synthetic utilityof AC was validated across a diverse set of mechanistic pathways,including C–H activation, radical relay, radical addition,and nucleophilic addition. We propose that AC can serve as a generaland robust platform to circumvent the persistent issue of metal catalystdeactivation in electrosynthesis. Overall, we have developed threestrategies from DC to AC electrosynthesis to address long-standingissues in electrochemical transition-metal catalysis. In contrastto the well-established DC electrosynthesis, the AC mode demonstratesa greater potential and diversity in transition-metal catalysis. Fullyexploiting the unique capabilities of AC to expand the applicationscenarios is of considerable scientific significance and practicalvalue.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3463–3480"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Modulated Circular Dichroism in Chiral Plasmonic Nanoparticles","authors":"Lichao Sun,&nbsp;Xuehao Sun,&nbsp;Qingfeng Zhang","doi":"10.1021/acs.accounts.6c00648","DOIUrl":"10.1021/acs.accounts.6c00648","url":null,"abstract":"&lt;p&gt;Plasmonic nanoparticles with an intrinsic chiralstructure haveemerged as pivotal platforms for exploring advanced chiroptical phenomena,with promising applications in asymmetric catalysis, chirality sensing,biomedicine, and spin optoelectronics. Distinct from organic chiralmolecules, chiral plasmonic nanoparticles exhibit strong and tunablecircular dichroism responses originating from structure-dependentlocalized surface plasmon resonance. Therefore, the structure of chiralplasmonic nanoparticles, including size, geometry, anisotropy, andtwinned structure, serves as the core determinant of their chiropticalperformance, such as spectral line shape and dissymmetry factor. However,quantitative insights into the correlation between particle structureand chiroptical activities are increasingly important yet presentsubstantial challenges. In this Account, we systematically elaborateon our recent efforts in establishing the fundamental principles ofstructure-dependent circular dichroism of chiral plasmonic nanoparticlesand their emerging applications in spin electrocatalysis, chiralityrecognition, and circularly polarized luminescence. First, we introduceour recent advances in the controlled synthesis of single-crystallinechiral plasmonic nanoparticles through a seed-mediated chiral growthmethod. Through a few cases, including bichiral geometry, concavevortex cube, and sub-100 nm chiral nanoparticles, we clarify the underlyingphysical mechanism of structure-modulated circular dichroism in chiralplasmonic nanoparticles. For instance, we proposed the bichiral centersin chiral Au nanoparticles, where the competition between 4-fold and3-fold chiral propellers leads to a tunable reversal of circular dichroismsignals without inverting the overall geometric handedness. Second,we highlight our success in the integration of high-order symmetrywith chiral geometry on individual twinned nanoparticles with increasingarchitectural diversity. Notably, starting with multitwinned (decahedraland icosahedral) seeds, we unlocked new classes of chiral plasmonicnanoparticles with 52 and 532 rotational symmetries, such as chiralpentagonal nanostars, pentagonal nanoprisms, and stellated nanoicosahedrons.These works demonstrated how twin boundaries and intrinsic latticestrain affect the evolution of geometric chirality as well as theiroptical chirality. Third, we showcase emerging applications of suchchiral plasmonic nanoparticles in (i) tuning oxygen electrocatalysisthrough the chiral-induced spin selectivity effect, (ii) enantioselectiverecognition through chiral surface-enhanced Raman scattering, and(iii) amplification of circularly polarized luminescence through chiralplasmonic nanocavities. Finally, we outline future directions andchallenges of chiral plasmonic nanoparticles with structure-modulatedcircular dichroism. It is envisioned that the controllable synthesisof chiral plasmonic nanomaterials with desired chiroptical activitiesnot only sheds light on the underlyi","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3576–3590"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metallapentalene-Fused Metallacyclopropenes: Synthesis, Reactivity and σ-Aromaticity","authors":"Yaowei Zhang,&nbsp;Shiqun Cheng,&nbsp;Hong Zhang,&nbsp;Haiping Xia","doi":"10.1021/acs.accounts.6c00594","DOIUrl":"10.1021/acs.accounts.6c00594","url":null,"abstract":"<p>Aromatic compounds are fundamentalto syntheticchemistry, biomedicine,and materials science. Among them, metallaaromatics─which incorporateat least one transition metal into an aromatic framework─representa distinctive class that has attracted substantial interest. The conceptof aromaticity, traditionally rooted in <em>π</em>-electrondelocalization, has been expanded by <em>σ</em>-aromaticity─firstproposed by Dewar in 1979 and subsequently established in all-metalclusters. Over the past decade, our group has developed a family ofmetal-centered conjugated polycyclic metallacycles termed carbolongcomplexes in which a carbon chain coordinates to a metal center viaa minimum of three metal–carbon bonds. These complexes exhibitremarkable stability towards water, oxygen, light, and heat, owingto polydentate chelation and aromatic stabilization.</p><p>This Accountsummarizes our systematic investigations into metallapentalene-fusedmetallacyclopropene derivatives─a unique subclass that integratesa highly strained three-membered ring into a robust aromatic scaffold.We describe our journey from the establishment of carbon-chain-basedframeworks via one-pot multiyne cyclizations to more elaborate carbolongskeletons through controlled [2+1] cycloadditions with isocyanidesand zinc carbenoids. Building on this carbon-rich platform, we extendedthe chemistry to peripheral <em>p</em>-block elements, incorporatingheteroatoms from groups 15, 16, and 17 into the metallacyclopropenecore to yield metalla-azirines, -phosphirenes, -chalcogenirenium,and -halirenium ions.</p><p>The fused metallacyclopropenes serve aspowerful synthetic intermediates,participating in formal [3+1], [3+2], and [3+3] cycloadditions toconstruct complex polycyclic architectures. The resulting materialsexhibit broad near-infrared absorption and high photothermal conversionefficiency and are promising for smart materials, drug delivery, andcancer phototherapy. Complementary computational studies have elucidatedtheir electronic structures. We established <em>σ</em>-aromaticity as a key stabilizing factor that counterbalances ringstrain─validating a long-debated concept and providing a designprinciple for stabilizing transient intermediates in transition-metalheterocycles. Systematic analyses of heteroatom-doped congeners revealclear periodic trends: the magnitude of <em>σ</em>-aromaticity─andconsequently the overall stability─is finely tuned by the electronicnature and size of the incorporated heteroatom. Ring strain energycalculations show that appropriate substitution can significantlyalleviate strain, reflecting the agreement between computation andexperiment.</p><p>Collectively, this work not only advances the fundamentalunderstandingof metallacyclic aromaticity but also paves the way for the rationaldesign of functional metallaaromatic materials with tailored properties.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3530–3544"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149092232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fragment-Based Design of Pesticide-Like Molecules: From Method Development to Agrochemical Discovery","authors":"Xing-Xing Shi,&nbsp;Zhi-Zheng Wang,&nbsp;Ruo-Qi Yang,&nbsp;Fan Wang,&nbsp;Guang-Fu Yang","doi":"10.1021/acs.accounts.6c00580","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00580","url":null,"abstract":"&lt;p&gt;Driven by rapid global population growth, anunprecedented demandfor food has placed severe pressure on agricultural production. Whilesynthetic pesticides have served as a cost-effective means of safeguardingcrop yields, the effectiveness of many existing agents is increasinglyundermined by rising pest resistance and stricter regulatory safetymargins, necessitating continuous innovation in more effective andsafer agrochemicals. Conventional agrochemical discovery relies onphenotypic screening directly against whole organisms, which requiressubstantial labor, funding, and time. Alternatively, target-basedapproaches using &lt;em&gt;in vitro&lt;/em&gt; assays have emerged asa powerful paradigm for the rational design of agrochemicals, increasinglysupported by computational strategies for ligand identification andoptimization. Thus, advancing computational methods for target-basedpesticide design is essential for accelerating the discovery of next-generationagrochemicals and supporting sustainable agriculture.&lt;/p&gt;&lt;p&gt;Fragment-baseddesign, a promising target-based approach developedprimarily in the pharmaceutical industry, can be extended to agrochemicalsdiscovery. By leveraging the additive binding contributions of molecularfragments to discrete protein subpockets, this technique enables smallmolecules to be optimized fragment by fragment, thereby significantlyexpanding chemical space for exploring novel bioactive scaffolds.The growing number of experimentally determined structures of agrochemicaltargets, together with rapid progress in protein structure modelingtechnologies, has provided valuable foundations for fragment-basedpesticide design. However, adapting the fragment-based strategy frompharmaceutical research to agrochemical discovery requires carefulconsideration of unique agrochemical molecular properties such asphotostability, ecotoxicity, and bioavailability. Therefore, the implementationof fragment-based agrochemical discovery still poses critical questions,such as how to acquire structurally diverse fragments that can bereadily assembled into pesticide molecules and how to assess the suitabilityof a fragment or ligand for subsequent optimization into pesticideleads.&lt;/p&gt;&lt;p&gt;In this Account, we describe our efforts to address theseissuesby incorporating the consideration of pesticide-likeness and ecotoxicityinto the fragment-based design pipeline and establishing an integratedcomputational framework for fragment-based agrochemical discovery.This framework supports key stages from fragment library design tofragment-to-lead optimization through a comprehensive suite of moleculartools, including (i) the qualitative and quantitative assessment methodsfor pesticide-likeness (HerbiPAD, InsectiPAD, FungiPAD, and Pesti-DGI-Net);(ii) the ecotoxicity predictive tools (beetox, AquaticTox, and PEAR)for rapid screening of eco-friendly candidates; (iii) the PADFragdatabase of pesticide- and drug-derived bioactive fragments, and theDigFrag method for &lt;em&gt;de novo&lt;/e","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3517–3529"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editing Enzymes with Multiscale Metal-Based Components","authors":"Xiaoyang Li,&nbsp;Richard N. Zare,&nbsp;Jun Ge","doi":"10.1021/acs.accounts.6c00338","DOIUrl":"10.1021/acs.accounts.6c00338","url":null,"abstract":"<p>Enzymes are powerful naturalcatalysts distinguishedby high efficiencyand selectivity. The use of enzymes in the chemical industry can theoreticallyenable numerous efficient and sustainable reaction pathways. Nevertheless,the application of enzymes is hindered by their narrow catalytic repertoire.Enzymes are readily deactivated under nonnatural environments, andtheir reaction types are limited. Developing enzymes with new catalyticfunctions has been a longstanding challenge in the field of biocatalysis.Strategies such as directed evolution and <em>de novo</em> protein design have been very successful in designing new enzymes.However, as both approaches rely on the engineering of amino acidsequences of proteins, they remain constrained and cannot fully meetthe growing demand for non-natural biocatalysis. Incorporating abioticcomponents with enzymes is a powerful tool for editing enzymes torender new catalytic capabilities. Metal-based components possessa broad catalytic repertoire, structural stability, and multifunctionality,making them promising building blocks for enzyme editing.</p><p>ThisAccount summarizes our contributions over the past decadein editing enzyme catalysts with metal-based components as a scale-dependentevolution, from nanoscale environmental modulation to atom-scale activesite redefinition, illustrating how enzyme editing with metal-basedcomponents can systematically address non-natural catalytic challenges.A conceptual framework in which enzymes are edited with metal-basedcomponents across scales from the nanometer to the atomic dimensionis introduced, establishing a logical basis for integrating biocatalysiswith abiotic reactivity. At the nanoscale, enzymes are encapsulatedin metal-based frameworks to improve the configuration stability,enabling catalysis under non-native and harsh conditions. The robustnessof enzymes under extreme pH, high temperature, and organic solventcan be largely enhanced through the regulation of metal-based frameworks.At the sub-nanoscale, metal clusters are embedded within enzyme scaffoldsto construct enzyme-metal hybrid catalysts. By integration of enzymaticand chemical catalysis, new non-natural catalytic processes can beestablished. At the atomic scale, metal atoms are incorporated intothe enzyme catalytic pocket, creating new hybrid active sites. Thehybrid active site endows an enzyme with capabilities to drive new-to-naturereactions, unlocking an expanded enzyme catalytic space. This workprovides a unifying conceptual framework that clarifies how metal-basedcomponents can be strategically employed to reprogram enzyme stability,functionality, and reactivity. We hope that the strategies and conceptsdiscussed herein offer comprehensive design principles for biohybridcatalysts and establish a foundation for reprogramming enzymatic functionbeyond evolutionary limitations.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3283–3293"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating Structural Heterogeneities of Amyloid Aggregates with Spatially Resolved Infrared Spectroscopy","authors":"Divya Baghel,&nbsp;Ayanjeet Ghosh","doi":"10.1021/acs.accounts.6c00390","DOIUrl":"https://doi.org/10.1021/acs.accounts.6c00390","url":null,"abstract":"&lt;p&gt;The aggregation of proteins into fibrillar amyloidsis centralto the pathology of neurodegenerative disorders. However, the relationshipbetween the structure of amyloid aggregates and disease progressionremains incompletely understood, in part because amyloid systems areintrinsically heterogeneous: structurally distinct species coexistat every stage of aggregation, and conventional ensemble-averagedmethods cannot always resolve them. This Account describes how infraredspectroscopy can be coupled to different imaging modalities to resolvethis heterogeneity at multiple length scales: from single-aggregatelevel to amyloid species in diseased brain tissues.&lt;/p&gt;&lt;p&gt;Our findingsdemonstrate that (i) early stage tau fibrils exhibitpronounced structural polymorphism without morphological differences,converging to a single dominant conformation upon maturation thatunexpectedly includes antiparallel β-sheet structure; (ii) Aβ42oligomeric heterogeneity propagates through protofibrils into fibrils,where structurally distinct domains coexist along a single fibril,demonstrating that amyloid fibrils can deviate significantly fromthe canonical parallel cross-β architecture; (iii) Aβ(16–22)fibrils undergo a parallel-to-antiparallel β-sheet transitionduring maturation through disordered intermediates without morphologicalchange, providing direct evidence of spontaneous structural reorganizationin fibrillar species. Beyond single-protein systems, (iv) Aβ42forms structurally distinct mixed polymorphs when aggregated withsequentially or structurally heterotypic seeds and when coaggregatedwith α-synuclein, establishing heterotypic interactions as anunderappreciated source of aberrant aggregate structures; (v) coaggregationof Aβ with the islet amyloid polypeptide (IAPP) from the monomericstate produces a unique heterotypic polymorph in which both peptidesadopt non-native structures, whereas cross-seeding with preformedIAPP fibrils yields predominantly homotypic Aβ aggregates, demonstratingthat conformational flexibility at the monomeric stage is requiredfor heterotypic fibril formation. These molecular-level findings arecomplemented by tissue-scale evidence: (vi) discrete frequency IRimaging reveals that amyloid plaques in AD brain exhibit chemicaland structural heterogeneities not reflected in morphology, consistentwith in vitro observations; and (vii) optical photothermal infrared(O-PTIR) spectroscopic imaging of vascular amyloid deposits in cerebralamyloid angiopathy (CAA) reveals a disease-stage-dependent increasein antiparallel β-sheet content that correlates specificallywith colocalized lipids, recapitulated in vitro by coaggregating Aβ40with lipid extracts. Collectively, these findings support the viewthat structural heterogeneity is not merely an artifact of in vitroconditions but a property that can persist in human brain tissuesand illustrate how spatially resolved IR spectroscopy can complementcryogenic electron microscopy (cryo-EM) and solid-state NMR in th","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"59 20","pages":"3294–3307"},"PeriodicalIF":18.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}