Volume 15 Issue 7, July 2023

Large language models such as ChatGPT have been predicted to lighten the load for some workers but make some roles obsolete. Michelle Francl explores what they can do for chemistry professors.

Genetic code expansion beyond α-amino acids is a major challenge, in which stitching together non-natural building blocks within the ribosome is a critical barrier. Now, the molecular determinants for the efficient incorporation of non-natural amino acids into the ribosome have been unlocked, accelerating ribosomal synthesis.

The concepts of multistep processes and regioselectivity — fundamental in covalent synthesis — have now been applied to the non-covalent synthesis of sequence-controlled multiblock supramolecular polymers.

Pharmacologically inactive prodrugs that can be activated by near-infrared light are attractive candidates for clinical applications. Now, platinum-based photo-oxidants have been shown to eradicate tumours in mice with a new mode of action.

The atomically precise assembly of metal nanoparticles offers vast possibilities for materials chemistry. Ring-shaped polyoxometalates have now served to stabilize Ag₃₀ nanoparticles with exposed surfaces.

Colloidal clathrate crystals self-assembled from hard polyhedral shapes in computer simulations are stabilized by entropy compartmentalization, whereby hosts and guests contribute unequally to the entropy. This creative solution to satisfying the laws of thermodynamics suggests new ways to make colloidal crystals with open cages and hierarchical host–guest structures.

Protein translation is the ultimate paradigm for sequence-defined polymer synthesis. To introduce non-canonical monomers into the genetic code of living organisms, pairs of biomolecules known as aminoacyl-tRNA synthetases (aaRSs) and transfer RNAs (tRNAs) are required. The discovery and engineering of five such pairs, that do not interfere with each other or the aaRS–tRNA pairs of a bacterial host, sets the stage for highly modified genetically encoded biopolymers.

Clathrates—open crystals with a hierarchy of polyhedral cages—are mostly found in atomic and molecular systems. Now, it has been shown through Monte Carlo simulations that the formation of colloidal host–guest clathrates can be driven by entropy alone, through entropy compartmentalization.

Genetic code expansion to incorporate non-α-amino acid monomers is limited by predictability of monomer reactivities in the context of the ribosome. Now the use of metadynamics simulations of pre-attack monomers in the ribosomal peptidyl transferase centre provides insight on whether an A-site monomer is likely to be reactive.

Supramolecular structures are typically formed by the one-step self-assembly of building blocks. Now, a greater level of control has been achieved using stepwise non-covalent reactions under kinetic control. Two-dimensional block supramolecular polymers with tailored compositions and sequences were synthesized, and a site selectivity that is reminiscent of regioselectivity in covalent synthesis was observed.

Conventional photo-driven cancer treatment agents require oxygen and visible light to induce cell death, limiting their efficacy in deep, oxygen-poor tumours. Now, a class of NIR-activatable Pt(IV) photooxidants that target the endoplasmic reticulum have been shown to effectively overcome these limitations by directly oxidizing intracellular biomolecules in an oxygen-independent fashion, presenting a promising new direction for next-generation metal-based drug development.

Atomically precise metal nanoclusters can serve a variety of purposes, yet their high reactivity also makes them difficult to synthesize. Now, well-defined {Ag₃₀} nanoclusters have been prepared within ring-shaped polyoxometalates. These nanoclusters show good stability in solution and the solid state, can undergo redox-induced structural transformation, and possess exposed surfaces that can serve as catalytically active sites.

Mutually orthogonal aminoacyl transfer RNA synthetase/transfer RNA pairs are required for genetically encoding non-canonical amino acids into proteins, as well as for the encoded cellular synthesis of polymers and macrocycles; however, the scalable discovery of such pairs is challenging. A quintuply orthogonal set of pyrrolysyl-tRNA synthetase/pyrrolysyl-tRNA pairs has now been generated through tRNA screening, engineering and directed evolution.

Ribosomal incorporation of non-α-amino acid monomers into proteins is largely restricted to in vitro translation. Now, pyrrolysyl-transfer RNA synthetase variants have been shown to acylate tRNAs with α-thio acids, malonic acids, and N-formyl amino acids. This work represents a key step towards the programmed ribosomal synthesis of sequence-defined non-protein polymers in cellulo.

In situ chirality identification for single-molecule systems is not a straightforward task. Now, real-time chirality identification during a Michael addition reaction has been realized by continuous measurements of spin-polarized currents through a single-molecule junction, providing a promising method for studying symmetry-breaking reactions.

The metallophilic interaction between cyclometalated palladium complexes can facilitate supramolecular nanostructure formation in living mice, providing a phototoxic prodrug with a long circulation time and high tumour-targeting efficiency. Upon green light irradiation, this palladium-based drug destroys solid tumours, leaving non-irradiated organs intact.

The diverse site-selective functionalization, including multi-functionalization, of C=C double bonds and C(sp³)–H bonds remains a largely unmet challenge. Now, a palladium-catalysed aerobic oxidative method has been developed for the multi-site programmable functionalization of terminal olefins via a strategy that controls the reaction sequence between alkene isomerization and oxidative functionalization.

In vitro screening of a ribosomally synthesized macrocyclic peptide library containing cyclic γ^2,4-amino acids (cγAA) afforded the discovery of potent inhibitors of the SARS-CoV-2 main protease (M^pro). A co-crystal structure revealed the contribution of this cγAA to M^pro binding and the proteolytic stability of these macrocycles.

Electronic spin influences chemistry profoundly, but its role in surface chemistry is poorly established. Now the spin-dependent reaction probabilities of oxygen atoms with a graphite surface have been studied. Molecular dynamics simulations help elucidate the mechanism for spin-flipping, which is observed to occur with low probability in surface scattering experiments.

Incorporating polar residues into hydrophobic protein channel pores facilitates selective proton transport. Now, classical and multiscale reactive molecular dynamics simulations of designed channels reveal dynamic water wires within the channel lumen that are proton conductive according to structural and functional validation. These results provide some guiding principles for biological and engineered proton conduction.

Ultra-high-capacity Li–air batteries have low Coulombic efficiency and degrade during re-charging, resulting in a poor cycle life. Redox mediators enable improvements but only at undesirably high potentials. The origin of this high potential and the impact of purported reactive intermediates has now been elucidated by resolving the charging mechanism using Marcus theory.

Cellular membranes contain numerous lipids, and efforts to understand the biological functions of individual lipids demand approaches for controlled modulation of membrane composition in situ. Now, click chemistry-based directed evolution of a microbial phospholipase within mammalian cells affords an editor for optogenetic, targeted modification of phospholipids in cell membranes.

Martin Johansen and Abhik Ghosh reflect on the unusual chemistry of carbones — whose central carbon atom bears two lone pairs — and their role as double-dative ligands.