Research articles

In 1949, Winstein and Trifan proposed that the 2-norbornyl cation adopts a bridged, non-classical structure. Now, the generation of an asymmetric environment around the three-centre two-electron bond of such an ion has been reported, enabling highly enantioselective catalytic addition reactions to a simple, non-functionalized non-classical cation.

High-accuracy quantum chemistry methods struggle with a combinatorial explosion of Slater determinants in larger molecular systems, but now a method has been developed that learns electronic wavefunctions with deep neural networks and reaches high accuracy with only a few determinants. The method is applicable to realistic chemical processes such as the automerization of cyclobutadiene.

Crystal symmetry is notoriously uncorrelated to the symmetry of the constituent molecules that make up a crystal. Symmetry breaking is typically thought to occur during nucleation and growth, but a symmetry element of olanzapine crystals—an inversion centre—has now been shown to emerge in centrosymmetric dimers extant in solution prior to crystallization.

Although azetidines represent highly desirable building blocks in drug discovery, methods for their efficient and straightforward synthesis remain underdeveloped. Now, it has been shown that highly functionalized azetidines can be prepared via an intermolecular [2+2] photocycloaddition reaction between cyclic oximes and alkenes, in a process enabled by a visible-light-mediated triplet energy transfer.

Despite the fundamental role of ATPase in catalysing ATP hydrolysis, the structural and energetic aspects of this process are not fully understood. Coarse-grained computational models have now been used to calculate the free-energy surfaces of different types of ATPases. The catalytic dwell is shown not to be crucial for movement against applied torque.

The vast majority of species capable of converting dinitrogen to ammonia rely on transition metals. Now, a boron compound has been shown to mediate the one-pot binding, cleavage and reduction of N₂ to ammonium salts under mild conditions through a complex cascade mechanism involving multiple reduction–protonation sequences.

A chemoenzymatic method to site-specifically conjugate peptide and protein thioesters to folded proteins at lysine residues has been developed. The method uses a genetically encoded four-residue tag that is recognized by the E2 SUMO-conjugating enzyme Ubc9. This approach enables isopeptide formation with just Ubc9 in a programmable manner and obviates the need for E1 and E3 enzymes.

Quantum machine learning with improved data efficiency and transferability has been achieved using on-the-fly selection of query-dependent training molecules, which are drawn from a ‘dictionary’ of atom-in-molecule-based fragments. The benefits of the resulting models have been demonstrated for important molecular properties and for systems including organic molecules, 2D materials, water clusters, DNA base pairs and ubiquitin.

A six-helix bundle DNA structure called meta-DNA has now been assembled and shown to possess some structural properties similar to those of single-stranded DNA. Two meta-DNAs containing complementary ‘meta-base pairs’ are shown to form double helices. Meta-DNA building blocks are also used to construct a series of DNA architectures and to perform a hierarchical strand-displacement reaction.

Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.

Crystal nucleation processes are difficult to probe experimentally because of the spatial and temporal scales involved. Now, the heterogeneous nucleation of three different metals has been observed by electron microscopy with atomic resolution—using single-walled carbon nanotube as test tubes—and, in each case, shown to adopt a two-step nucleation mechanism involving a metastable amorphous precursor.

A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A.

Transient metallonitrenes (M–N) have been proposed as key intermediates in nitrogen atom transfer reactions, but well-defined examples have remained elusive. Now, a platinum complex with an atomic nitrogen ligand, best described as a subvalent nitrogen diradical singly bonded to a platinum(ii) ion (Pt–N), has been isolated and shows ambiphilic reactivity.

Cyclic β-amino acids can add useful properties to peptides, such as inducing turn structures or providing resistance to proteases. To harness these properties up to ten consecutive cyclic β-amino acids have now been ribosomally incorporated via genetic code reprogramming into a foldamer peptide library that has been screened for potent binders against a protein target, human factor XIIa.

A series of enzymes that catalyse the formation of strained peptide cyclophanes through a stereospecific C(sp²)–C(sp³) bond have been identified. Crosslinking occurs on three-residue motifs that include tryptophan or phenylalanine to form indole- or phenyl-bridged cyclophanes. These enzymes are widely distributed in nature and represent promising tools for peptide biotechnology.

White phosphorus (P₄) is very reactive but is relatively difficult to activate without relying on transition metals. Now, it has been shown that the degradation of P₄ can be mediated by two divalent silicon atoms in a bis(silylene) scaffold to give a diphosphorus complex that can be further functionalized and also act as a P⁻ transfer agent.

Patterns formed by artificial out-of-equilibrium chemical oscillating networks (such as the Belousov–Zhabotinsky reaction) are difficult to control with any precision. Now, it has been shown that low-intensity audible sound can be used to generate spatiotemporal patterns with a programmable distribution of redox- and pH-responsive chemical systems and supramolecular assemblies in solution.

Class II terpene cyclases convert simple linear substrates into complex polycyclic compounds, which typically requires multiple protein domains. Now, a single-domain class II cyclase, a cyanobacterial merosterolic acid synthase, has been identified and characterized. High-resolution X-ray crystal structures provide detailed insights into how a minimalistic enzyme accomplishes this complex cyclization process.