Articles

Highly-charged intrinsically disordered proteins (IDPs) underpin biomolecular condensate formation, however, the influence of charge sequences on the dynamics within the condensate phase remains underexplored. Here, the authors use molecular dynamics simulations with explicit hydrodynamics and electrostatics to study the dynamics in IDP condensates across different length and time scales by varying the charge sequences of the constituent IDPs, showing that hydrodynamic and electrostatic effects are strongly coupled to the IDP charge sequence, in contrast with the expectation of long-range interactions being heavily screened.

Photocatalysis holds promise for sustainable synthesis, but AI-driven reaction prediction is hindered by limited data. Here, the authors introduce PhotoCatDB, a comprehensive database of 26.7 K reactions, and develop PhotoCat, a transformer-based tool achieving high accuracy in photocatalytic reaction prediction, retrosynthesis, and condition recommendation, as well as experimentally validate the newly discovered photocatalytic reactions.

Oncogenic PI3Kα variants are key drivers of tumorigenesis; however, the conformational landscape of these mutants is not well characterized. Here, the authors use atomistic molecular dynamics simulations to show that double mutations in PI3Kα induce significant conformational shifts, revealing cryptic druggable pockets within PI3Kα and providing a rationale for using allosteric drug combinations in targeted therapy.

Amyloid fibril formation from amyloid-beta peptides is a key feature of Alzheimer’s disease, yet the mechanisms of its spatial and temporal spread remain unclear. Here, the authors reveal that amyloid-beta 42 aggregation propagates via diffusion of oligomers in solution, highlighting these species as key drivers of the spatial spreading of aggregation.

Water vibrational motion, which occurs on the few-femtosecond timescale and underpins energy transfer within the hydrogen bonding network, has remained challenging to observe in real time due to constraints in time resolution. Here, the authors investigate the ground state vibrational dynamics of liquid water using a sub-5 fs near-infrared pump pulse and few-fs ultraviolet probe pulses, observing rapid dephasing of the OH stretch mode that precedes its relaxation via coupling to the bend modes.

Cryogenic electron microscopy (cryo-EM) single-particle analysis is a powerful method for macromolecular structure determination, however, its effectiveness is often constrained by limited particle numbers or missing views. Here, the authors introduce CoCoFold, a framework integrating cryo-EM images with AlphaFold, employing a fused attention mechanism for enhanced atomic model prediction and a differentiable network for end-to-end refinement against experimental data.

TEAD transcription factors are critical effectors and druggable sites of the Hippo pathway in cancer, however, the development of small molecule inhibitors and degraders remains underexplored. Here, the authors identify and characterize bifunctional IAP-based degraders targeting TEAD1 via a lipid pocket and recruit different members of the inhibitor of apoptosis proteins (IAPs) family, offering a comprehensive toolkit for structural, biophysical and cellular profiling.

DNAzymes rely on dissolved metal ions as cofactors for catalytic activity, however, the effects of metals in heterogeneous systems are not fully understood. Here, the authors demonstrate that metal surfaces can directly activate DNAzymes at solid-liquid interfaces, revealing a mechanism involving superoxide anions.

Deoxyhypusine synthase (DHS) is central to hypusination and plays an important role in cellular physiology and disease, yet strategies to modulate its activity and regulate the hypusination process remain largely lacking despite detailed knowledge of its enzymatic mechanism. Here, the authors employ crystallographic fragment screening to identify fragments with the potential to regulate DHS, revealing their binding sites and underlying regulatory mechanisms.

Human serum transferrin plays a crucial role in iron homeostasis, but its interaction with potential metallodrugs remains underexplored. Here, the authors solve the X-ray structure of an adduct between transferrin (Fe_C-hTF) and [V^V₂O₆]^2–, generated from a vanadium-based drug [V^IVO(acac)₂], showing that binding preserves the overall conformation of Fe_C-hTF.

Spherulites, prevalent in fields from geology to medicine, have poorly understood crystallization dynamics and growth conditions. Here, the authors demonstrate that divalent metal ions in sulfate salt solutions induce spherulitic growth of sodium sulfate through non-classical nucleation, revealing high viscosity and slow dynamics as key factors.

Transient Receptor Potential Melastatin 3 (TRPM3) is a non-selective, Ca²⁺-permeable ion channel that plays a pivotal role in the peripheral and central nervous systems; however, the effect of cellular redox state on the TRPM3 activity is unknown. Here, the authors reveal that TRPM3 channel activity is bidirectionally modulated by oxidizing and reducing agents, and identify cysteine residues in the extracellular pore loop of TRPM3 that carry the redox-control of the channel.

Protein–protein interactions often rely on the folding of intrinsically disordered regions (IDRs) during complexation. Here, the authors reveal how small molecule AM-7209 induces folding of the MDM2 oncoprotein’s IDR through non-polar interactions, by combining molecular dynamics simulations, calorimetry and NMR measurements.

Hydrogen-assisted dehydrochlorination (HaDHC) is an attractive route for the production of fluorine-containing olefins under relatively mild conditions, but highly efficient metal-based catalysts for this reaction remain underexplored. Here, the authors report a nano-MgF2-supported Pd-Ag catalyst with tunable Pd dispersion that is optimized by tuning of the Pd-Ag alloy degree in the fresh catalyst, followed by in situ restructuring, and demonstrate its performance in the HaDHC of 1,1,1,2-tetrafluoro-2-chloropropane (HCFC-244bb) to 2,3,3,3-tetrafluoropropene (HFO-1234yf), a hydrofluoroolefin refrigerant with reduced global warming impact.

Charged polymer interactions alter the structure and dynamics of surrounding water molecules, with implications in biological and technological applications, but studying these interactions across a broad concentration range has remained challenging. Here, the authors combine angle-resolved second harmonic scattering, dynamic light scattering, nuclear magnetic resonance, and molecular dynamics simulations to investigate the interactions between hyaluronan (HA) and different oligopeptides, observing selective, multivalent binding between HA and cationic peptides that induce solvent and solute restructuring as well as nanoscale dynamic clustering.

Reactive carbonyl compounds pose toxicity challenges as pollutants and metabolites; however, synthetic scavengers for detoxification remain underdeveloped. Here, the authors demonstrate that 1-amino-but-3-enes, particularly those with phenyl groups, selectively scavenge formaldehyde and glyoxylic acid, offering potential for biomedical applications.

Enzymes offer a sustainable solution for recycling polyethylene terephthalate (PET) waste, however, their efficiency remains limited for large-scale applications. Here, the authors use QM/MM MD simulations to reveal the depolymerization mechanism of a cutinase variant, uncovering dynamic internal electric fields that stabilize transition states and lower the energy barrier, offering a strategy to engineer high-performance PET hydrolases.

Bicyclic peptides targeting integrin are promising drug candidates, yet achieving high selectivity for specific integrins remains challenging. Here, the authors design RGD-containing bicyclic peptides with a tryptathionine bridge, demonstrating that peptide 5j selectively targets integrin αvβ3, and induces αvβ3-targeted cytotoxicity by drug-peptide conjugates.

Biosynthetic colourants are sustainable alternatives to replace artificial dyes, but prediction of their optical properties remains challenging. Here, the authors develop a workflow combining message passing neural networks and excited state calculations to predict colour changes at different pH levels, offering a promising tool for designing eco-friendly dyes.

Nucleic acid-based therapy and diagnosis require improved methods for synthesising stable oligonucleotide conjugates. Here, the authors introduce a method for direct functionalization of various amino-modified oligonucleotides (AONs), enabling dual-functionalization of AONs and the synthesis of fluorescent peptide-oligonucleotide conjugates.