ACS Central Science最新文献

Nature provides access to biological catalysts that can expand the chemical transformations accessible to synthetic chemists. Among these, α-ketoglutarate, non-heme iron-dependent (NHI) enzymes stand out as scalable biocatalysts for catalyzing selective oxidation reactions. Many NHI enzymes require protein engineering to improve their activity, selectivity, or stability. However, the reliance of this strategy on the innate stability of the enzyme can thwart the success of the engineering campaign. Harnessing innately stable enzymes can overcome these challenges and accelerate biocatalyst engineering. Herein, we highlight the use of ancestral sequence reconstruction (ASR) to mine for thermostable enzymes that can serve as superior starting points for protein engineering. In our effort to develop a biocatalytic route to tropolones, we identified an NHI enzyme that demonstrated poor stability, diminished activity at high substrate concentrations, and a limited substrate scope. We compared the in-lab evolution of the modern NHI enzyme and its ancestor, demonstrating the improved evolvability profile of the latter. By engineering the ancestral protein, we accessed variants with enhanced thermostability and expression, increased rates, and a substrate scope broader than those of their modern counterparts. Altogether, this work provides a strategy to rapidly access enzyme backbones that can accelerate engineering of more robust and synthetically useful NHI enzymes.

Ancestral α-ketoglutarate, non-heme iron dependent enzymes provide more robust backbones with enhanced evolvability, thermostability, and activity toward the formation of tropolone scaffolds.

Tunneling control of chemical reactions is treasured as the third reactivity paradigm, next to kinetic and thermodynamic control. However, reports on the successful observation and mechanistic insight into quantum tunneling in conventional heterogeneous catalysis are limited. By using an atomically dispersed palladium catalyst, we now demonstrate room-temperature catalytic hydrogenation dominated by concerted triple hydrogen tunneling. While a large kinetic isotope effect value of ∼2440 is observed in the benzyl aldehyde hydrogenation when both H₂ and solvent (CH₃OH) are deuterated, the use of protic solvent is important to achieve enhanced catalysis. Systematic investigations reveal that, with a protic solvent molecule situated between the catalytic site and aldehyde, the formation of a local hydrogen bond network helps to induce the concerted triple hydrogen tunneling, namely, that two protons transfer from the ligand on the catalytic site to the mediated solvent and the oxygen of C═O on aldehyde, respectively, and the other transfers from Pd on the catalytic site to the carbon of C═O on aldehyde. With the width and height of the potential energy barrier alterable by protic solvents, the hydrogen tunneling probability can be regulated by solvents. Furthermore, far-infrared irradiation is found to enhance the hydrogenation rate.

This work demonstrates a room-temperature catalytic hydrogenation governed by concerted triple hydrogen tunneling, allowing its regulation with hydrogen-bond networks and far-infrared irradiation.

Proteins achieve diverse biological functions through precise sequence-structure relationships, yet they can also function through statistical ensembles rather than as individual, static entities. Inspired by this paradigm, recent work has explored random heteropolymers (RHPs) as synthetic, scalable, and versatile protein mimetics. RHPs have been found to function as polymer ensembles capable of folding, binding, catalyzing, and stabilizing biomolecules with control over the monomer sequence. In this Outlook, we highlight recent advances in the discovery and mechanistic understanding of functional RHPs, emphasizing their emergent behaviors and utility across sustainability, human health, and pharmaceuticals. We discuss how autonomous experimentation, machine learning, and multiscale modeling are converging to accelerate design and discovery in this vast chemical space. By embracing statistical design principles, we propose a new framework for creating functional polymers that mirror biological systems.

Recent discoveries enabled by diverse strategies on random heteropolymers reveal emergent protein-like functions, paving the way for new catalysts, biomaterials, and sustainable technologies.

RNA–protein interactions are critical for cellular processes, including translation, pre-mRNA splicing, post-transcriptional modifications, and RNA stability. Their dysregulation is implicated in diseases such as myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). To investigate RNA–protein interactions, here is described a live-cell NanoBioluminescence Resonance Energy Transfer (NanoBRET) assay to study the interaction between expanded r(CUG) repeats [r(CUG)^exp] and muscleblind-like 1 (MBNL1), central to DM1 pathogenesis. This r(CUG)^exp sequesters MBNL1, a regulator of alternative pre-mRNA splicing, in nuclear foci causing splicing dysregulation. In the NanoBRET assay, r(CUG)^exp acts as a scaffold to bring into proximity a BRET pair, MBNL1–NanoLuciferase (NanoLuc) and MBNL1–HaloTag, enabling a quantitative readout of RNA–protein interactions. Following assay optimization, an RNA-focused small molecule library was screened, identifying ten compounds with shared chemotypes that disrupt the r(CUG)^exp–MBNL1 complex. Nuclear magnetic resonance (NMR) studies revealed these inhibitors bind to the 1 × 1 UU internal loops formed when r(CUG)^exp folds. Five of these molecules rescued two cellular hallmarks of DM1 in patient-derived myotubes, alternative pre-mRNA splicing defects and formation of nuclear r(CUG)/MBNL1-positive foci. These results demonstrate that the NanoBRET assay is a powerful tool to study RNA–protein interactions in live cells and to identify small molecules that alleviate RNA-mediated cellular pathology.

Live-cell NanoBRET probes RNA−protein interactions and identifies small molecules that disrupt the toxic r(CUG)^exp−MBNL1 complex, alleviating pathology in myotonic dystrophy type 1 (DM1).

Reactive strand extension decouples toughness from modulus in single- and double-network gels.

Advances in bioinformatics have enabled the discovery of unique enzymatic reactions, particularly for ribosomally synthesized and post-translationally modified peptides (RiPPs). The recently discovered daptides, peptides with their C-terminus replaced by an amine, represent one such case, but the diversity, requirements, and engineering potential of daptide biosynthesis remain to be established. Using the daptide biosynthetic gene clusters from Thermobifida fusca and Streptomyces azureus, we reconstituted daptide biosynthesis in vitro, revealing the enzymatic requirements for successive oxidative decarboxylation, transamination, and N,N-dimethylation. In vitro and in vivo studies showed a tailoring family of YcaO enzymes convert a secondary amine intermediate to a C-terminal imidazoline. We further demonstrated enzymatic activity toward shortened, leader peptide-free, and non-native core peptides, highlighting a broad substrate tolerance. Using these insights, we directed the daptide pathway to install new C-termini, including a bioconjugation-compatible aminoacetone, on various peptide and protein substrates.

Daptide biosynthetic enzymes convert C-termini to aminoacetone, diaminopropane, dimethylimidazoline, etc. and can install these modifications onto a broad range of substrates.

Oxidative methane coupling (OCM) has long been deemed a promising route for the direct conversion of methane to valuable ethylene. Despite its potential and many progresses, OCM’s industrial implementation has been hampered by low C₂ yields and insufficient understanding of the reaction mechanism for catalyst design. In this study, we present a surface geometric modification strategy to enhance OCM performance. Single La atoms incorporated onto MgO surface (SA-La/MgO) form a unique La–O–Mg “slingshot” geometry. This configuration, driven by the large atomic radius of La and its valency mismatch with Mg, significantly activates surface lattice oxygen. These activated oxygen species initiate the OCM by reacting with methane, while the resulting oxygen vacancies are rapidly replenished by dioxygen, sustaining active oxygen supply and preserving the structural integrity of single La atoms. These processes are realized by state-of-the-art in situ environmental electron microscopy and electron energy loss spectroscopy. Remarkably, the La–O–Mg “slingshot” geometry doubles C₂ yields and significantly elevates the turnover frequency of SA-La/MgO compared to La₂O₃ particles on MgO, which lacks such active oxygen species. This work discovers a new mechanism for largely enhancing the OCM performance, emphasizing the importance of atomic-scale geometric and electronic modifications in catalyst design.

Atomic-scale La−O−Mg geometry enhances OCM performance by activating lattice oxygen, offering new insights into catalyst design through in situ electron microscopy.

Earth-abundant ligand-to-metal charge transfer (LMCT) chromophores in donor–acceptor dyads unlock an electron transfer pathway for efficient triplet state formation.

A quantum algorithm navigating the immense design space of multivariate porous materials demonstrates a logical and practical roadmap for the future of chemical synthesis.