JACS Au最新文献

{"title":"Activation and Allostery in a Fungal SAMHD1 Hydrolase: An Evolutionary Blueprint for dNTP Catabolism","authors":"Luying Pan,&nbsp;Jake C. Lachowicz,&nbsp;Isaac Paddy,&nbsp;Yutong Xu,&nbsp;Qianyi Yang,&nbsp;Cynthia Zizola,&nbsp;Amy Milne,&nbsp;Tyler L. Grove* and Maria-Eirini Pandelia*,&nbsp;","doi":"10.1021/jacsau.5c0009010.1021/jacsau.5c00090","DOIUrl":"https://doi.org/10.1021/jacsau.5c00090https://doi.org/10.1021/jacsau.5c00090","url":null,"abstract":"<p >Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a metal-dependent hydrolase that plays key roles in dNTP homeostasis, antiretroviral defense, and regulation of various cancers in humans. Beyond mammals, SAMHD1 is also present in a wide range of eukaryotes, including invertebrates, plants, and human parasites. Although the specific mechanisms and biological significance of SAMHD1 in these organisms are not well understood, its functions are linked to essential processes such as photosynthesis, genome maintenance, and immune response. In this study, we bioinformatically mined the SAMHD1 superfamily and selected the ortholog from the mycorrhizal fungus <i>Rhizophagus irregularis</i> as a model system for both fungal and biochemically intractable plant SAMHD1s. <i>Ri</i> SAMHD1 retains the substrate promiscuity of the human enzyme but bypasses the strict requirement for allosteric activation through tetramerization, positioning it as a prototypical enzyme in which hydrolysis and allosteric regulation can be uncoupled. Its activity is selectively dependent on transition metal ions such as Mn and Fe, while Mg serves as a poor activator. Although <i>Ri</i> SAMHD1 lacks several ancillary regulatory features present in human SAMHD1, its activity is differentially modulated by GTP, which acts as an allosteric activator at lower concentrations and an allosteric inhibitor at higher concentrations. These results demonstrate that metal dependence and allosteric regulation are adaptive traits that have evolved divergently among mammals, fungi, and plants, invoking alternative molecular routes for fine-tuning dNTP levels. Our findings on <i>Ri</i> SAMHD1 provide a paradigm for the mechanistic diversification of SAMHD1 enzymes and offer valuable insights for dissecting the complex mechanisms of nucleotide regulation in humans.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1862–1874 1862–1874"},"PeriodicalIF":8.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthesis and Antigenic Evaluation of Oligosaccharides of Bordetella hinzii O-Antigen Containing Unique Amidated 2,3-Diacetamido-2,3-dideoxy-alduronic Acids","authors":"Lin Zhang,&nbsp;Zhichao Zheng,&nbsp;Yumeng Zhang,&nbsp;Xiaopei Wu,&nbsp;Yuanhong Tu,&nbsp;Can Liu,&nbsp;Zhen Wang,&nbsp;Liming Wang*,&nbsp;You Yang* and Qingju Zhang*,&nbsp;","doi":"10.1021/jacsau.5c0011310.1021/jacsau.5c00113","DOIUrl":"https://doi.org/10.1021/jacsau.5c00113https://doi.org/10.1021/jacsau.5c00113","url":null,"abstract":"<p ><i>Bordetella hinzii</i> is a zoonotic pathogen, which can cause brain abscess, pneumonia, bacteremia, and urinary tract infection. Vaccines are economical and effective means for combating infectious diseases. Herein, we present the first total synthesis of the highly functionalized mono- and oligosaccharides of <i>B. hinzii</i> O-antigen for vaccine development. The rare 2,3-diacetamidopyranoses were generated from 3-<i>O</i>-acetyl-2-nitroglycals via an organocatalyzed one-pot relay glycosylation method. The postglycosylation oxidation strategy was used to overcome the poor reactivity of 2,3-diacetamido-aldouronic acid building blocks in glycosylation reactions. Direct amidation of alduronic acid with NH₃ in the late stage reduced the protecting group operation and increased the synthetic efficiency. Di-<i>tert</i>-butylsilylidene-directed α-galactosylation method was used to construct challenging 1,2-<i>cis</i>-glycosidic bond. Six oligosaccharides of <i>B. hinzii</i> O-antigen were obtained and further conjugated to human serum albumin for antigenicity evaluation (the sera antibodies were obtained from vaccinated mouse via inactivated <i>B. hinzii</i>). The terminal tetrasaccharide of <i>B. hinzii</i> O-antigen has been identified as a potential glycol-epitope and might be useful for vaccine development against <i>B. hinzii</i>.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1903–1913 1903–1913"},"PeriodicalIF":8.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00113","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878261","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ru-Catalyzed Polyethylene Hydrogenolysis under Quasi-Supercritical Conditions","authors":"Sungmin Kim,&nbsp;Boda Yang,&nbsp;Oliver Y. Gutiérrez,&nbsp;Wei Zhang,&nbsp;Carlos Lizandara-Pueyo,&nbsp;Piyush Ingale,&nbsp;Ivana Jevtovikj,&nbsp;Reni Grauke,&nbsp;Janos Szanyi,&nbsp;Huamin Wang,&nbsp;Stephan A. Schunk and Johannes A. Lercher*,&nbsp;","doi":"10.1021/jacsau.5c0000610.1021/jacsau.5c00006","DOIUrl":"https://doi.org/10.1021/jacsau.5c00006https://doi.org/10.1021/jacsau.5c00006","url":null,"abstract":"<p >Ru/C-catalyzed polyethylene (PE) and hydrocarbon hydrogenolysis under quasi-supercritical fluid of isopentane was kinetically and mechanistically investigated. PE hydrogenolysis with C–C and C–H cleavage showed zeroth order, suggesting strong adsorption of hydrocarbons. PE yielded broad product distribution of heavy (C_21–40) and diesel-range (C_11–20) hydrocarbons in the primary step of hydrogenolysis due to stochastic C–C cleavage over Ru surface. Catalytic hydrogenolysis of <i>n</i>-hexadecane, squalane, and light hydrocarbons such as <i>n</i>-pentane, iso-pentane, and <i>n</i>-hexane further described C–C cleavage reactivity between primary and secondary carbons, i.e., ¹C–²C and ²C–²C, which has an order of magnitude higher hydrogenolysis rate than that involving a tertiary carbon. The PE saturated Ru surface and lower C–C cleavage reactivity of tertiary carbon in iso-pentane, therefore, imited sovlent conversion during hydrogenolysis, whereas leading to selective PE conversion. Using hexadecane, we observed comparable hydrogenolysis rates between H₂ and D₂ (<i>k</i>_H<i>/k</i>_D ∼ 1), indicating the kinetically relevant step of C–C cleavage with facilitating C–H cleavage and rehydrogenation. However, the normal kinetic isotope effect between hexadecane and deuterated hexadecane (<i>k</i>_{C₁₆H₃₄}<i>/k</i>_{C₁₆D₃₄} ∼ 5) revealed that the dehydrogenation, i.e., C–H cleavage, can be kinetically involved in the hydrogenolysis kinetic. By considering the 8-fold lower H-D exchange rate with deuterated hexadecane compared to n-hexadecane, the lower rate for hydrogenolysis and H-D exchange with deuterated hexadecane can be attributed to the C–D bond dissociation energy being 3 kJ/mol higher than that of the C–H bond. Increasing H₂ pressure favors internal C–C bond cleavage over terminal one. This minimizes the formation of lower hydrocarbons, particularly methane. However, the increase in H₂ pressure increases the coverage of adsorbed hydrogen on the Ru particles due to competitive adsorption of H₂ and polyethylene, which, in turn, reduces the polyethylene conversion rates.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1760–1770 1760–1770"},"PeriodicalIF":8.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"l-2,3-Diaminopropionate Binding Mode of the SulM Adenylation Domain Limits Engineering Monobactam Analogue Biosynthesis with Larger Substrates","authors":"Lukas Kahlert,&nbsp;Ketan D. Patel,&nbsp;Michael S. Lichstrahl,&nbsp;Rongfeng Li,&nbsp;Chengkun He,&nbsp;Andrew M. Gulick* and Craig A. Townsend*,&nbsp;","doi":"10.1021/jacsau.5c0023110.1021/jacsau.5c00231","DOIUrl":"https://doi.org/10.1021/jacsau.5c00231https://doi.org/10.1021/jacsau.5c00231","url":null,"abstract":"<p >The simple but essential azetidinone core of the β-lactam antibiotics is uniquely N-sulfonated in the monobactam subfamily. This feature confers both target binding specificity to inactivate bacterial cell wall biosynthesis (antibiosis) and structural differentiation to elude destruction by metallo-β-lactamases (MBLs). The recent FDA approval of Emblaveo to treat serious bacterial infections combines an established synthetic monobactam aztreonam and avibactam, which additionally blocks serine β-lactamases, to create a broadly effective antibacterial therapeutic. Here we report experiments to capture the native monobactam biosynthetic steps to the natural product sulfazecin with the aim of accessing new monobactams by reprogramming its biosynthetic machinery. In sulfazecin biosynthesis, the β-lactam ring is formed by a nonribosomal peptide synthetase SulM that incorporates <span>l</span>-2,3-diaminopropionate (Dap), which is then N-sulfonated in trans and efficiently cyclized to the fully elaborated monobactam by an unusual thioesterase (TE) domain. We describe an improved synthesis of (2<i>S</i>,3<i>R</i>)-vinylDap to support rational structure-based engineering experiments to obtain the corresponding (4<i>R</i>)-vinyl sulfazecin. While these experiments were initially based on an AlphaFold model of the adenylation domain that incorporates Dap (SulM A3), we further report high-resolution X-ray crystal structures with both the <span>l</span>-Dap substrate and an accurate analogue of the activated (3<i>R</i>)-methyl-Dap adenylate bound. The ligand-bound structures rationalize the inability of SulA3 to incorporate larger substrates. Comparisons with the structures of other diamino acid-activating adenylation domains identify alternate binding modes that may be more suitable for the production of sulfazecin analogues. The impact of these structures on the further engineering of the SulA3 domain and its relation to monobactam synthesis in the recently structurally characterized SulTE are discussed.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1992–2003 1992–2003"},"PeriodicalIF":8.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Unsaturated Cu1–O3 Coordination to Boost Oxygen Species Activation for Low-Temperature Catalysis in CO Oxidation","authors":"Yadi Wang,&nbsp;Zeyu Jiang,&nbsp;Fan Dang,&nbsp;Chaoqian Ai,&nbsp;Jialei Wan,&nbsp;Chunli Ai,&nbsp;Yani Wu,&nbsp;Chi Ma,&nbsp;Mingjiao Tian,&nbsp;Han Xu,&nbsp;Reem Albilali,&nbsp;Weisheng Guan,&nbsp;Hongna Zhang* and Chi He*,&nbsp;","doi":"10.1021/jacsau.4c0114910.1021/jacsau.4c01149","DOIUrl":"https://doi.org/10.1021/jacsau.4c01149https://doi.org/10.1021/jacsau.4c01149","url":null,"abstract":"<p >The activation of lattice oxygen at low temperatures is essential for heterogeneous catalytic oxidation, but exactly how this is achieved by adjusting the coordination structure of atomic sites is still elusive. Herein, the Cu₁O₃–CeO₂ catalyst with highly dispersed unsaturated Cu₁–O₃ coordination was creatively engineered, which remarkably enhanced the low-temperature oxidation of CO (a typical model reaction) from 12% to 90% at 66 °C compared to conventional CuCeO_<i>x</i> catalyst. The preservation of atomic coordination-deficient Cu sites enables the transfer of electron cloud density from Cu atoms to O atoms, hence, facilitating the activation of lattice oxygen. Further electron transfer from O atom to Cu species results in charge back-donation to form sufficient Cu⁺ and metal per-oxy species, contributing to weaken O–O bonds. We determined that the increasing number of electron donors induced by unsaturated atomic Cu₁–O₃ coordination is an efficient strategy to develop highly active and stable catalysts for lattice oxygen activation. The catalyst synthesis strategies and oxygen activation mechanism demonstrated in this work provide a generalizable platform for the future design of well-defined functional catalysts for low-temperature oxidation reactions.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1677–1688 1677–1688"},"PeriodicalIF":8.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c01149","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrocatalytic Ammonia Oxidation by a Ruthenium Complex Bearing a 2,6-Pyridinedicarboxylate Ligand","authors":"Jun Li,&nbsp;Xiaohuo Shi,&nbsp;Feiyang Zhang,&nbsp;Xingyu Lu,&nbsp;Yaqiong Zhang,&nbsp;Rongzhen Liao* and Biaobiao Zhang*,&nbsp;","doi":"10.1021/jacsau.5c0005410.1021/jacsau.5c00054","DOIUrl":"https://doi.org/10.1021/jacsau.5c00054https://doi.org/10.1021/jacsau.5c00054","url":null,"abstract":"<p >Molecular catalysts for the electrocatalytic ammonia oxidation reaction (eAOR) have much to offer in terms of mechanistic investigations and practical energy issues. This work reports the use of complex [Ru(pdc-κ-N¹O²)(bpy)(NH₃)] (<b>Ru-NH</b>_<b>3</b>) (H₂pdc = 2, 6-pyridinedicarboxylic acid; bpy = 2,2′-bipyridine) bearing a readily accessible pdc^2– ligand to catalyze ammonia oxidation under electrochemical conditions. The rich structural variations of <b>Ru-NH</b>_<b>3</b> in coordinating solvents and an ammonia atmosphere were fully characterized by cyclic voltammograms (CVs), NMR, and XRD. CV experiments showed that <b>Ru-NH</b>_<b>3</b> promotes electrocatalytic ammonia oxidation at a low overpotential of 0.85 V with a calculated catalytic rate (<i>k</i>_obs) of 18.9 s^–1. Controlled potential electrolysis (CPE) at an applied potential of 0.3 V vs Fc^+/0 achieves 76.1 equiv of N₂ with a faradaic efficiency of 89.8%. Experimental and computational analyses indicated that oxidation of <b>Ru-NH</b>_<b>3</b> generates a reactive <b>Ru</b>^<b>III</b><b>-NH</b>_<b>3</b> intermediate, which undergoes sequential electron and proton transfer steps to form a <b>Ru</b>^<b>VI</b><b>≡N</b> species. N–N bond formation occurs via the nucleophilic attack of an ammonia molecule on the <b>Ru</b>^<b>VI</b><b>≡N</b> moiety with a facile barrier of 8.6 kcal/mol. Eventually, N₂ evolved as the product after releasing two electrons and three protons.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1812–1821 1812–1821"},"PeriodicalIF":8.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer Cell Identification via Lysosomal Membrane Microviscosities Using a Green-Emitting BODIPY Molecular Rotor","authors":"Ru̅ta Bagdonaitė,&nbsp;Rokas Žvirblis,&nbsp;Jelena Dodonova-Vaitku̅nienė and Artu̅ras Polita*,&nbsp;","doi":"10.1021/jacsau.5c0025310.1021/jacsau.5c00253","DOIUrl":"https://doi.org/10.1021/jacsau.5c00253https://doi.org/10.1021/jacsau.5c00253","url":null,"abstract":"<p >Lysosomes are dynamic, membrane-bound organelles that play key roles in cellular waste disposal, macromolecule recycling, and signaling. Disruptions in lysosomal function and lipid composition are implicated in a wide range of diseases including lysosomal storage disorders, fatty liver disease, atherosclerosis, and cancer. Imaging of the lysosomal lipid composition has the potential to not only enhance the understanding of lysosome-related diseases and their progression but also help identify them. In this work, we present a novel viscosity-sensitive, green-emitting BODIPY probe that can distinguish between ordered and disordered lipid phases and selectively internalize into the lysosomal membranes of live cells. Through the use of fluorescence lifetime imaging microscopy, we demonstrate that lysosomal membranes in multiple cancer cells exhibit significantly higher microviscosities compared to noncancer cells. The differences in lysosomal microviscosities provide an effective approach for identifying cancer cells and indicate that malignant cells may possess more oxidized and saturated lysosomal lipid membranes. Furthermore, we demonstrate the utility of viscosity-sensitive probes in quantifying the compositional changes in lysosomal membranes by investigating the effects of lysosome-permeabilizing cationic amphiphilic drugs (CADs), sertraline, and astemizole. Our results reveal that despite their functional similarities, these CADs exert opposite effects on lysosomal microviscosities in both cancerous and noncancerous cells, suggesting that different mechanisms may contribute to the CAD-induced lysosomal damage and leakage.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"2004–2014 2004–2014"},"PeriodicalIF":8.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00253","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking Novel δ and φ Bonding Modes in Actinides via Oxidation State Control","authors":"Maria J. Beltran-Leiva,&nbsp;Enrique R. Batista* and Ping Yang*,&nbsp;","doi":"10.1021/jacsau.4c0127710.1021/jacsau.4c01277","DOIUrl":"https://doi.org/10.1021/jacsau.4c01277https://doi.org/10.1021/jacsau.4c01277","url":null,"abstract":"<p >Understanding the principles that govern actinide–ligand (An–L) bonding is essential for advancing practical applications in nuclear industry and environmental protection, as well as for deepening our fundamental knowledge of actinide chemistry. Modifying the symmetry or softness of the coordinating ligand, or altering the metal center, are common strategies to modulate the energy and orbital overlap in An–L interactions, driving both experimental and computational research efforts toward greater control over covalency. On the metal side, reducing the oxidation state causes the f- and d-orbitals to become more diffuse and destabilized. This not only enhances covalency when coordinated to suitable ligands but also opens the door to novel bonding modes via metal-to-ligand back-donation which despite their potential for advancing separation chemistry, remain largely underexplored. On the ligand side, symmetry plays a critical role in controlling the types of bonding modes. In this work, we demonstrate that variations in actinide oxidation state across the early actinide series can be used as a lever to selectively activate or suppress back-bonds. By selecting three ligands─allyl, cyclocumulene, and cyclopropene─each possessing symmetries conducive to δ and φ back-bond formation, we identified a previously elusive φ “head-to-head” back-bond. This interaction emerged as the strongest in uranium and protactinium diallyl complexes, surpassing the φ back-bonds observed in cyclooctatetraene (COT) systems. Additionally, an extension of the Dewar-Chatt-Duncanson model to f-elements is proposed. These findings not only advance our fundamental understanding of actinide bonding but also open new pathways for 5f-electrons-driven chemistries.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1746–1759 1746–1759"},"PeriodicalIF":8.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.4c01277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Reveals Amine Type in Polymer Micelles Determines mRNA Binding, In Vitro, and In Vivo Performance for Lung-Selective Delivery","authors":"Sidharth Panda,&nbsp;Ella J. Eaton,&nbsp;Praveen Muralikrishnan,&nbsp;Erin M. Stelljes,&nbsp;Davis Seelig,&nbsp;Michael C. Leyden,&nbsp;Alexandria K. Gilkey,&nbsp;Jackson T. Barnes,&nbsp;David V. Morrissey,&nbsp;Sapna Sarupria,&nbsp;Branden S. Moriarity and Theresa M. Reineke*,&nbsp;","doi":"10.1021/jacsau.5c0008410.1021/jacsau.5c00084","DOIUrl":"https://doi.org/10.1021/jacsau.5c00084https://doi.org/10.1021/jacsau.5c00084","url":null,"abstract":"<p >Cationic micelles, composed of amphiphilic block copolymers with polycationic coronas, offer a customizable platform for mRNA delivery. Here, we present a library of 30 cationic micelle nanoparticles (MNPs) formulated from diblock copolymers with reactive poly(pentafluorophenol acrylate) backbones modified with diverse amines. This library systematically varies in nitrogen-based cationic functionalities, exhibiting a spectrum of properties that encompass varied degrees of alkyl substitution (A1–A5), piperazine (A6), oligoamine (A7), guanidinium (A8), and hydroxylation (A9–A10) that vary in side-chain volume, substitution pattern, hydrophilicity, and p<i>K</i>_a to assess parameter impact on mRNA delivery. <i>In vitro</i> delivery assays using GFP+ mRNA across multiple cell lines reveal that amine side-chain bulk and chemical structure critically affect performance. Using machine learning analysis via SHapley Additive exPlanations (SHAP) on 180 formulations (3780 experimental measurements), we mapped key relationships between amine chemistry and performance metrics, finding that amine-specific binding efficiency was a major determinant of mRNA delivery efficacy, cell viability, and GFP intensity. Micelles with stronger mRNA binding capabilities (A1 and A7) have higher cellular delivery performance, whereas those with intermediate binding tendencies deliver a higher amount of functional mRNA per cell (A2, A10). This indicates that balancing the binding strength is crucial for performance. Micelles with hydrophobic and bulky pendant groups (A3–A5) tend to induce necrosis during cellular delivery, highlighting the significance of chemical optimization. A7 amphiphile, displaying primary and secondary amine, consistently demonstrates the highest GFP expression across various cell types and <i>in vivo</i> achieves high delivery specificity to lung tissue upon intravenous administration. Moreover, we established a strong correlation between <i>in vitro</i> and <i>in vivo</i> performance using Multitask Gaussian Process models, underscoring the predictive power of <i>in vitro</i> models for anticipating <i>in vivo</i> outcomes. Overall, this innovative study integrates advanced data science with experimental design, demonstrating the pivotal role of chemical amine-dependent optimization for advancing targeted mRNA delivery to the lungs.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"1845–1861 1845–1861"},"PeriodicalIF":8.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DFT-CES2: Quantum Mechanics Based Embedding for Mean-Field QM/MM of Solid–Liquid Interfaces","authors":"Taehwan Jang,&nbsp;Seung-Jae Shin,&nbsp;Hyung-Kyu Lim,&nbsp;William A. Goddard III and Hyungjun Kim*,&nbsp;","doi":"10.1021/jacsau.5c0017610.1021/jacsau.5c00176","DOIUrl":"https://doi.org/10.1021/jacsau.5c00176https://doi.org/10.1021/jacsau.5c00176","url":null,"abstract":"<p >The solid–liquid interface plays a crucial role in governing complex chemical phenomena, such as heterogeneous catalysis and (photo)electrochemical processes. Despite its importance, acquiring atom-scale information about these buried interfaces remains highly challenging, which has led to an increasing demand for reliable atomic simulations of solid–liquid interfaces. Here, we introduce an innovative first-principles-based multiscale simulation approach called DFT-CES2, a mean-field QM/MM method. To accurately model interactions at the interface, we developed a quantum-mechanics-based embedding scheme that partitions complex noncovalent interactions into Pauli repulsion, Coulomb (including polarization), and London dispersion energies, which are described using atom-dependent transferable parameters. As validated by comparison with high-level quantum mechanical energies, DFT-CES2 demonstrates chemical accuracy in describing interfacial interactions. DFT-CES2 enables the investigation of complex solid–liquid interfaces while avoiding extensive parametrization. Therefore, we expect DFT-CES2 to be broadly applicable for elucidating atom-scale details of large scale solid–liquid interfaces for multicomponent systems.</p>","PeriodicalId":94060,"journal":{"name":"JACS Au","volume":"5 4","pages":"2047–2058 2047–2058"},"PeriodicalIF":8.5,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/jacsau.5c00176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}