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The chemosensing accuracy of E. coli cells is shown to be limited by internal noise in signal processing, rather than the stochasticity of molecule arrivals at their receptors, contrary to long-held understanding in the field.

The SARS-CoV-2 Nucleocapsid (N) protein serves multiple roles in the viral lifecycle. Phosphorylation toggles N between these roles by altering N’s conformation, its material properties when phase separated with RNA, and its membrane interactions.

A multi-laboratory study finds that single-molecule FRET is a reproducible and reliable approach for determining accurate distances in dye-labeled DNA duplexes.

The combination of single-molecule fluorescence detection with Förster resonance energy transfer provides a powerful probe of biomolecular dynamics on timescales ranging from nanoseconds to days. This Review outlines single-molecule Förster resonance energy transfer spectroscopy with a focus on dynamics and highlights future developments and enhanced capabilities.

By combining single-molecule spectroscopy, nanophotonic enhancement, and molecular simulations, the authors reveal the extremely rapid chain dynamics of single-stranded nucleic acids.

Histone H1 binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. Now it has been shown that the disordered regions of H1 retain their large-amplitude dynamics on the nucleosome, which enables a charged disordered histone chaperone to invade the H1–nucleosome complex and vastly accelerate H1 dissociation.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

The interaction between the polyelectrolytic IDP ProTα and a highly charged folded protein domain is investigated by integrating NMR, single-molecule FRET and MD simulations. Net charge and charge distribution are implicated in binding and selectivity.

The Panoptes antiphage system defends bacteria by detecting phage-encoded counter-defences that sequester cyclic nucleotide signals, triggering membrane disruption and highlighting a broader strategy of sensing immune evasion through second-messenger surveillance.

Two highly charged disordered human proteins phase-separate into viscous complex coacervates while retaining their rapid conformational dynamics through pico- to nanosecond exchange of short-lived side-chain interactions.

Energy funnelling within multichromophoric assemblies is key to the conversion of solar energy by plants. Now, energy transport between phthalocyanine-based chromophores has been monitored at the submolecular level using scanning tunnelling microscopy, focusing on the role of ancillary, passive and blocking chromophores in promoting and directing energy transfer between distant donor and acceptor units.

Broad uptake of smFRET has been hindered by high instrument costs and a lack of open-source hardware and acquisition software. Here, the authors present the smfBox, a cost-effective open-source platform capable of measuring precise FRET efficiencies between dyes on freely diffusing single molecules.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

The unusual properties of entangled photons endow them with useful properties for imaging and metrology tasks. This work simulates the use of entangled photons for controlling two-exciton states in Blastochloris viridis, showing their advantages for studying excitation pathways in bacterial reaction centres.

Individual protein dynamics can be studied in live eukaryotic cells from the millisecond to nanosecond level using an integrated approach to confocal single-molecule FRET spectroscopy.

RNA chaperones, such as the hepatitic C virus (HCV) core protein, are proteins that aid in the folding of nucleic acids. Here authors use single‐molecule spectroscopy and simulation to show that the HCV core protein acts as a flexible macromolecular counterion which facilitates nucleic acid folding.

An international blind study confirms that smFRET measurements on dynamic proteins are highly reproducible across instruments, analysis procedures and timescales, further highlighting the promise of smFRET for dynamic structural biology.

Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double strand-break (DSB) repair, directly re-ligates broken DNA ends with minimal errors. In this study, the authors identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) that prioritize ligation and promote NHEJ fidelity.

How interactions between binding partners form or break is hidden in the transition paths from the encounter to the formation of a stable complex. Here authors use single‐molecule spectroscopy to measure the transition path times for the association of two intrinsically disordered proteins that form a folded dimer upon binding and identify a metastable encounter complex.

High-phylogenetic-resolution microbiome mapping by fluorescence in situ hybridization (HiPR-FISH) enables the spatial mapping of hundreds of species of microorganisms and shows how microbial networks in the mouse gut are affected by antibiotic treatment.

A high-affinity complex of histone H1 and prothymosin-α reveals an unexpected interaction mechanism, where the large opposite net charge enables the two proteins to remain highly disordered even in the complex.

Traditional scintillators face challenges in achieving fast response and avoiding afterglow. Guzelturk et al. report colloidal quantum shell heterostructures with bright multiexciton emission, enabling efficient, fast, and robust scintillation for high-resolution and high-speed X-ray imaging.

Studies on protein–protein interactions using proteins containing d- or l-amino acids show that stereoselectivity of binding varies with the degree of disorder within the complex.

Cryogenic electron microscopy determines the structure of a fully assembled, MR1-reactive, human Vγ8Vδ3 TCR–CD3δγε₂ζ₂ complex bound by anti-CD3ε antibody Fab fragments.

IgE molecules associate with the FcɛRIα receptor in an acutely bent conformation where the Cɛ2 domains fold over the Cɛ3-Cɛ4 domains. A new study demonstrates that IgE can exist in an extended conformation with a Cɛ2 domain capable of flipping from side to side, suggesting a level of structural flexibility that could functionally impact allergen recognition.

Two red fluorescent proteins with long Stokes shift enable simultaneous multicolor 2p imaging. CyRFP1 is well-suited for 2p structural imaging, and FRET sensors made with mCyRFP1 and mMaroon1enable multicolor 2pFLIM in brain slices. Also online, a paper by Bajar et al. reports the development of mMaroon1.

Pore-forming toxins are expressed as monomers and assemble into multimeric pores. Here, Benke et al. follow the kinetics of pore formation for the bacterial toxin ClyA with single-molecule methods and show that pore formation progresses through the assembly of oligomeric intermediates, rather than by the addition of monomers to a nascent pore.

Internal friction affects the kinetics of protein folding. Borgiaet al. investigate how this friction affects the folding dynamics of the protein spectrin, revealing a potential role in the rate-limiting conformational changes.

Adherens junctions mediate force transmission and connect the cytoskeleton of adjacent cells. This study demonstrates that force transmission can be achieved through direct and functional β-catenin/vinculin interaction in the absence of α-catenin.

Nanopore electrical detection has shown potential in sensing subtle protein and peptide conformation changes, and its sensitivity makes it promising for point-of-care applications. In this Review, the authors discuss the capability of nanopore sensing for detecting and quantifying conformational modifications and enantiomers in biomarker proteins and peptides, as well as the practicalities and challenges for this approach to be used for clinical and point-of-care diagnosis.

Conformation-specific antibodies and longitudinal tracking of individual neurons in situ identifies a toxic monomer species linked to Huntington's disease.

K⁺ plays an important role in physiology and disease, but the lack of high specificity K⁺ sensors limits our understanding of its spatiotemporal dynamics. Here the authors develop genetically-encoded FRET-based probes able to quantify K⁺ concentration in body fluids, cells and specific organelles.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

In this work, the authors unveil a mechanism where the Citron homology domain regulates HPK1’s kinase domain, shedding light on the relationship between HPK1’s structure and function. This enhances our understanding of HPK1, an intracellular target for cancer immunotherapy and provides a direction for immuno-oncology drug discovery.

Cytotoxic response is mediated by delivery of lytic molecules at the effector cell/target cell junction site, termed the immunological synapse. Here the authors find, using single cell biophysical measurements, that the during this process the αLβ2 integrin, LFA-1, helps focus lytic granule release via talin-dependent, pulling force-mediated spatial guidance.

Telomerase uses its associated RNA as a template for processive addition of telomeric DNA repeats. Biochemistry and smFRET analysis are now used to investigate how the RNA template moves along the active site, revealing an accordion mechanism whereby the regions flanking the template alternate between extended and compacted forms.

Droplet-based microfluidics enable rapid mixing with millisecond dead times and allow single-molecule measurements of non-equilibrium binding kinetics on even challenging, strongly adsorptive samples, such as intrinsically disordered proteins.

Raman and fluorescence spectra, consistent with several species of aromatic organic molecules, are reported in the Crater Floor sequences of Jezero crater, Mars, suggesting multiple mechanisms of organic synthesis, transport, or preservation.

A quantum system that super-radiates must also exhibit enhanced absorption, but the former always dominates in natural systems. However, by invoking environmental quantum control techniques, Higgins et al.demonstrate that a system can exhibit quantum-enhanced light absorption.

Single molecule kinetics investigations and molecular simulations are useful tools in elucidating protein assembly mechanisms. Here, the authors use these to show that even naturally occurring tandem repeats undergo transient misfolding and that assembly is much more complex than we previously understood.

The emission properties of quantum dots make them ideal for probing plasmonic nanostructures, but their small size makes them difficult to manipulate. Ropp et al.use a microfluidic system to accurately place single quantum dots around silver nanowires to probe the local density of optical states.

The Varkud satellite ribozyme, which catalyses site-specific RNA cleavage and ligation, is an important model to understand RNA catalysis. Now, a combination of theoretical and experimental work has revealed new details about its catalytic mechanism. Mg²⁺ is shown to play an important role in organizing the active site, and the proton transfers in the transition state have also been identified.

Biogenesis of small nucleolar RNAs ribonucleoproteins (snoRNPs) requires dedicated assembly machinery. Here, the authors show that a subset of snoRNP assembly factors interacts, genetically or directly, with factors modulating chromatin architecture, suggesting a link between ribosome formation and chromatin functions.