ACS Central Science最新文献

Combining bioorthogonal protecting groups with localized catalysts that can unmask them is a powerful approach to spatially and temporally modulate molecular activity. Enzymes are appealing catalysts in this context because they are genetically targetable, but enzymes are not always available to unmask a protecting group of interest. Here, we report a platform for ultrahigh-throughput enzyme evolution by combining yeast surface display with masked acylating probes, which selectively label yeast cells based on target biocatalytic activity. We introduce the phenylcyclopropyl (pCP) ester protecting group, which has improved bioorthogonality compared to existing ester protecting groups, and use our platform to evolve BS2 esterase for enhanced pCP unmasking. Evolved BS2 mutants are up to 232-fold more active toward the pCP group. Taking advantage of the enhanced bioorthogonality of the pCP group, we applied a pCP probe together with evolved BS2 to perform spatially resolved RNA tagging with high spatial specificity, including in mammalian cell lines with high endogenous esterase activity. Overall, this work delivers a new bioorthogonal protecting group and engineered enzymes capable of unmasking it, and more broadly, it provides a platform to rapidly engineer enzymes for protecting group removal, opening opportunities in imaging, proximity tagging, induced cell signaling, and therapeutics.

Most optogenetic tools are controlled by blue light. Red-light-responsive tools enable multiwavelength applications and allow greater biological tissue penetration with reduced toxicity. Current red-light tools are primarily based on phytochromes, large dimeric proteins with a structurally complex mode of interaction with their binding partners. Here we introduce a small red-light-only responsive system composed of a BNp-Red-1.2 (6 kDa) that binds to a cyanobacteriochrome (CBCR) GAF domain NpF2164g6 (17 kDa) with a K_d ≈ 1–5 μM to form a 1:1 complex in the dark. Red light causes dissociation of the complex by causing a > 25-fold decrease in binding affinity. The CBCR GAF domain reverts to the dark state with a half-life of ∼ 1 min and the complex reforms. Structural analysis using NMR measurements combined with molecular docking and dynamics simulations shows that the binder interacts with the GAF domain and senses isomerization of the bilin chromophore at a site that overlaps the critical tongue domain of phytochromes. This system provides a small, simple red-light-only optogenetic tool that can operate to control protein–protein interactions in vitro and in living cells.

Hydrogen cyanide (HCN) is present in many astrochemical environments, including interstellar clouds and comets. On Saturn’s moon Titan, large amounts of HCN ice are present in the atmosphere and, following surface deposition, may influence both chemical and geological evolution. However, despite HCN’s relevance to origin of life chemistry, the physiochemical properties of its solid state remain poorly characterized. For example, the crystals of HCN exhibit a range of rare properties, including pyroelectricity, and the ability to glow and jump under certain conditions. Here we use quantum chemical methods to predict HCN crystal surface energies, from which we derive the needle-like, high-aspect-ratio morphology of HCN nanocrystals. The predicted tips expose high-energy polar facets imbued with strong electric fields. We suggest that the combination of tips of opposite polarity helps to explain the cobweb-structure of solid HCN, and that fracture can transiently expose energetic surfaces, capable of catalysis at low temperature. One such process is predicted to be the near-barrierless formation of isocyanide (HNC) on HCN crystals, following proton addition or abstraction, for example, via radiation or acid/base-chemistry. Such field-assisted surface mechanisms may contribute to HCN-to-HNC isomerization under relevant conditions, and are suggested to explain part of the out-of-equilibrium abundance of HNC in cold environments such as Titan’s atmosphere, and, potentially, in cometary comae.

Andrew Oddy looks back on his career as Keeper of Conservation at the British Museum and the exposure test that bears his name.

Despite the vast diversity of B cell repertoires, serum antibody responses during viral infection often focus on a limited set of epitopes─a phenomenon known as immunodominance. This inherent bias establishes a hierarchy of epitope responses, which often facilitates viral immune evasion and presents a major challenge for universal vaccine design. It remains unclear whether serum immunodominance is primarily driven by antigen-intrinsic properties or by the spatial constraints imposed by virion-bound antigen presentation. Here, using Ebola virus glycoprotein (GP) as a model system, we found that trimeric GP elicited varied epitope hierarchies between individual animals during primary immunization. In contrast, multivalent GP presentation on either a vesicular stomatitis virus or ferritin nanoparticles─in the native orientation found on the Ebola virus─elicited highly consistent and more refined epitope hierarchies across multiple mice and guinea pigs. These findings reveal a key role of oriented multivalent presentation in shaping serum immunodominance. The striking consistency of epitope hierarchy among individuals suggests that oriented multivalent presentation may promote more uniform immune protection at the population level, beyond increasing the magnitude of antibody binding and neutralizing responses.

The atomically precise nature of coinage-metal nanoclusters (CMNs) enables systematic exploration of structure–property relationships and motivates application oriented inverse design. However, the synthesis of CMNs typically relies on trial-and-error methods, with atomic-level structures only revealed through crystallography (postsynthesis), posing a major challenge to the deterministic synthesis of predesigned cluster structures, which is known as inverse synthesis. Here, we introduce CoLiM, a deep neural network framework that predicts the chemical compatibility between the unexplored inorganic core and ligands before synthesis. CoLiM employs a dual-encoder architecture and is trained on a newly constructed dataset comprising 1,989 reported CMN structures, supplemented by an additional gas-phase cluster dataset. The optimal CoLiM model achieves an area under the curve (AUC) exceeding 0.83 on a held-out test set, outperforming all of the baseline methods. To demonstrate its practical utility, CoLiM is applied to address the long-standing challenge of achieving atomically precise structural tailoring. Starting from [Cu₂₀Cl(PET)₁₂(PPh₃)₄(MeCOO)₆]⁺, we successfully performed single-atom editing on its inorganic core to synthesize [Cu₁₉Cl(PET)₁₂(PPh₃)₃(HCOO)₆] guided by the prediction of CoLiM, validating the model’s generalizability under real experimental conditions. Our framework facilitates the inverse synthesis and precise atomic-level modification of nanoclusters, underscoring its substantial potential to accelerate rational nanocluster discovery.

Visible photons carry significantly more energy than the thermal energies typically used to overcome activation barriers in conventional chemistry. This thermodynamic advantage enables photochemical reactions that are inaccessible from electronic ground states. However, photochemistry also faces a kinetic challenge: excited states are inherently short-lived, necessitating rapid reactivity before their decay. In this Outlook, we explore the unique interplay of thermodynamics and kinetics in molecular photochemistry. We highlight current limits and knowledge gaps and propose directions for advancing the conceptual framework of photocatalysis. Topics include the design of photocatalysts with extreme redox potentials, the use of solvated electrons and visible-to-UV upconversion, and the potential to bypass Kasha’s rule for higher-energy photochemical processes. Our aim is to survey strategies for pushing the boundaries of photocatalysis and to inspire future conceptual innovation in the field.

Mechanochemistry enables the preparation of the fundamental ortho-phosphite [PO₃]³⁻ anion from condensed phosphates.

DNA-encoded libraries (DELs) have become a powerful platform in drug discovery, practiced both by the pharmaceutical industry and academia. Each small molecule contained in a DEL is covalently linked to a DNA tag which serves as an amplifiable barcode facilitating binder identification. However, the chemical diversity accessible in DELs remains limited by the need to perform reactions under conditions that preserve the integrity of the DNA tag. Additionally, chemical reactions must proceed with high efficiency and selectivity to minimize side products and unreacted starting materials, which cannot be removed and may hamper hit identification. Consequently, expanding the DEL chemical space requires the development of methods that combine high reaction performance with DNA compatibility. In this outlook, we highlight the potential of enzymatic catalysis for on-DNA synthesis, which offers a promising route to expand DEL-accessible chemical space.

Mixing is essential in chemical processes, ensuring the proximity and interaction of reactants. Recent reports suggest stirring may minimally affect some solution-phase organic reactions, but this oversimplifies mixing’s complexity. We discuss its principles, relevance to organic synthesis, and practical considerations for reproducibility and safety. Even if some reactions seem agitation-insensitive, mixing remains crucial for reproducibility, scalability, and industrial applications.