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Engineering motif-specific 'hot spots' into an antibody scaffold yields antibodies with high affinity to targets containing phosphoserine, phosphothreonine or phosphotyrosine.

Current treatment of fungal infections is threatened by emerging antifungal drug resistance. In this work, the authors explore the synergistic activity of a host defense peptide mimetic, brilacidin, with caspofungin against a panel of fungal strains.

Foldamers are small molecules or oligomers that can adopt secondary and tertiary structures due to noncovalent interactions. Here, the authors show that an amphiphilic foldamer can adopt a hollow truncated octahedron crystal structure comprising of 48 individual foldamer units.

Nature's speciality is to direct and control the reactivity of species, which are otherwise fatally destructive. However, the processes and design rules required to achieve such precise control are not clear. A de novo designed metalloprotein that stabilizes an otherwise unstable organic radical has now been developed to guide our understanding.

Cyclic and mirror-image variants of de novo-designed proteins effectively bind and clear small-molecule drugs in vivo in less than 30 min, highlighting the applicability of computational tools to produce protein antidotes.

Amyloid fibrils can adopt a range of distinct conformations, yet it is challenging to rapidly discriminate between these polymorphs. Now methods have been developed to screen large, diverse libraries of turn-on fluorescent dyes to rapidly identify probes that recognize fibril subsets.

Structural analysis reveals how certain designed peptides adopt unusual spiraling cross-α amyloid-like structures and also rearrange to helical polymers upon mutation of small nonpolar residues that are critical for packing and stabilization.

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.

Self-assembly enables complex structures to be fabricated from a few relatively simple components, but requires a detailed understanding of how the constituents may interact. Here, the authors report the rational assembly and crystallographic characterization of a fullerene-protein superstructure.

Representing the first successful rational reprogramming of function in a de novo protein, the reactivity of a designed di-iron carboxylate protein from the Due Ferri family was altered from hydroquinone oxidation to arylamine N-hydroxylation through the introduction of a critical third histidine ligand in the active site.

Deep mutational scanning reveals that α-synuclein adopts a membrane-bound α-helix conformation with increasing dynamics towards the C terminus. This helical conformation is associated with its cytotoxicity.

The first demonstration of a protein designed entirely from first principles that binds a small-molecule cofactor in a precisely predetermined orientation has now been described. The design method utilizes a remote protein core that both anchors and predisposes a flexible binding site for the desired cofactor-binding geometry.

The self-propagation of misfolded conformations of tau occurs in neurodegenerative diseases, including Alzheimer's disease. The microtubule-binding region, tau_244-372, reproduces much of the aggregation behaviour of tau in cells and animal models. Now, it has been shown that a 31-residue peptide from tau's R3 domain forms a cross-β conformation that efficiently seeds aggregation of tau_244-372 in cells.

Amyloid fibril formation is often catalysed by mature fibrils or other aggregates on the fibrillization pathway; however, fibrils cannot normally catalyse other chemical reactions. Here, small seven-residue peptides designed from first principles are shown to form amyloid fibrils that can efficiently catalyse ester hydrolysis.

The study demonstrates that specific recognition and custom binding geometries can be computationally encoded between protein spans within lipids through designing synthetic transmembrane proteins to functionally regulate a target cytokine receptor.

The de novo design of functional membrane proteins is a formidable challenge. Now, water-soluble peptides have been designed that assemble into α-helical barrels with accessible, polar and hydrated central channels. Insights from these structures have been used to produce stable membrane-spanning, cation-selective channels.

Peptide-based supramolecular assemblies are a promising class of nanomaterials with important biomedical applications, but their antibacterial properties can be overlooked. Here the authors show the antibacterial activity of self-assembled diphenylalanine, which emerges as the minimal model for antibacterial supramolecular polymers.

The antiviral drugs amantadine and rimantadine target the M2 protein of influenza A virus, making an understanding of its structure important for the study of drug resistance. The results of a recent crystal structure of M2 differ from those of a solution NMR structure with regards to binding of these drugs, indicating a different mechanism of inhibition in each case. Here, using solid-state NMR spectroscopy, two different amantadine-binding sites are shown to exist in the phospholipid bilayers of M2.

Understanding the mode of small-molecule binding to amyloid filaments is critical for diagnosing and treating neurodegeneration. The authors use cryo-EM to reveal a stacked binding motif which may hasten design of diagnostics and therapeutics.

Arrigoni et al. present non-canonical voltage-gated ion channel pore domain (PD) structures demonstrating that the PD is an autonomously folded unit found in diverse proteins and show that PDs can adopt non-canonical forms in full-length channels.

Infrared fluorescent proteins offer advantages for deep in vivo imaging thanks to the tissue-penetrating properties of infrared light. Here, Yu et al. design a monomeric infrared fluorescent protein that, when combined with expression of haeme oxygenase in cells, shows improved performance for in vivoimaging of neurons and brain tumours.

SNAC-tags allow for versatile sequence-specific cleavage of soluble and membrane proteins with Ni²⁺ under biocompatible conditions, bypassing enzymatic cleavage and enabling cleavage in situations where commonly used enzymes fail.

The significance of hydrogen bonds in protein structure was recognized as early as 1936 by Mirsky and Pauling, and the importance of hydrogen bonds in water-soluble proteins has since been studied extensively. Now a new paper takes an important step forward in characterizing the energetic significance of hydrogen bonds in membrane-soluble proteins.

Proteins associate via weak and transient interactions that are challenging to identify in vivo. Here, the authors use a genetically encoded chemical cross-linker to covalently lock interacting proteins in live cells, allowing them to identify the captured proteins by mass spectrometry.

This Review describes the de novo design of metalloproteins, which perform numerous functions essential to life. By understanding the relationship between the symmetry of the protein structure and the metal active site, we can design novel, functional metalloproteins from scratch.

A series of bacterial receptor proteins have been 'redesigned' by computer so that they bind molecules that are quite different from their natural ligands. The approach might be useful for designing catalytic proteins.

A vital component of influenza A virus' replication machinery is the M2 proton channel. Until recently, M2 was effectively targeted by amantadane-based antivirals, but resistance to these drugs is now so widespread that they have become ineffective. In the second of two related manuscripts, the crystal structure of a 25-residue fragment of M2, both with and without amantadine, is described. It is concluded that a single amantadine molecule binds in the centre of the M2 tetramer to physically occlude the pore.