ACS Central Science最新文献

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.

An electron-enriched PtNiCo catalyst enabled by TiN support boosts stability in methanol fuel cells by simultaneously overcoming CO poisoning and metal dissolution.

Antimicrobial resistance remains a formidable challenge to modern medicine, with bacterial resistance mechanisms increasingly eroding the utility of clinically important antibiotics. While recent efforts have expanded the antibacterial pipeline, the development of resistance in priority pathogens continues to exceed the pace of new drug development. One emerging strategy to overcome resistance is the rational design of hybrid antibiotics that engage multiple binding sites. Here we describe the design, synthesis, and microbiological and structural characterization of hybrid antibiotics of azithromycin, tedizolid, and chloramphenicol that span the peptidyltransferase center (PTC) and nascent peptide exit tunnel (NPET) in the bacterial ribosome. We characterize the binding of four such hybrids by cryo-electron microscopy, granting insight into their molecular mechanisms of action. We identify a hybrid of azithromycin and tedizolid that is active against a diverse panel of multidrug-resistant Gram-positive bacteria and is minimally affected by ribosomal protection (ABC-F) resistance mechanisms. These results extend our understanding of ribosome inhibition and provide a pipeline for the rational design of dual-action antibiotics that target the ribosome. In a broader context, this work offers a framework for developing bifunctional inhibitors that engage adjacent binding sites by means of a rational cycle of synthetic optimization, biological evaluation, and structural characterization.

An integrated platform to develop hybrid antibiotics that inhibit the bacterial ribosome.