We offer a new labeling approach to introduce isolated 15N−13C−1H spin systems to the side chains of arginine residues. The labeling scheme delivers high-resolution NMR spectra to study large protein....

Protein folding models have achieved groundbreaking results typically via a combination of integrating domain knowledge into the architectural blocks and training pipelines. Nonetheless, given the suc...

Abstract. Recently, a novel tobramycin-responsive riboswitch was developed by a combination of Capture-SELEX and in vivo screening. This riboswitch regulat

Side chain stapling of cysteine (Cys) residues offers convenient entry into constrained peptides with enhanced bioactivity and bioavailability. Despite its widespread application in the constraint of α-helical, PPII, and loop conformations, the stabilization of β-sheet folds via intrastrand side chain Cys stapling remains largely unexplored. Here, we demonstrate that i→i+2 stapling with E-butenyl, butynyl, and m-xylyl linkers significantly enhances the folded population of two distinct β-hairpin model peptides. High-resolution NMR structures reveal that these staples support canonical β-sheet backbone torsions and stabilize cross-strand interactions. Leveraging the maintenance of intact backbone hydrogen-bonding edges, we employed i→i+2 side chain macrocyclization in the design of constrained β-arch peptides derived from the tau protein. We show that intrastrand stapling of a nonaggregation-prone segment promotes self-assembly into β-sheet-like filaments. The resulting filaments also seed the aggregation of endogenous tau in a cell-based assay in a macrocycle- and sequence-dependent manner. These findings establish di-Cys i→i+2 stapling as a versatile and synthetically accessible method to stabilize β-sheet structure and modulate the self-assembly of seed-competent amyloidogenic peptides.

A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prio...

Using RFdiffusion, a general method for targeting intrinsically disordered proteins and regions for protein design has been developed.

The increase in antibacterial resistance is one of the greatest challenges in modern medicine, driving an urgent need to develop new drugs to combat resistant pathogens. Peptides represent a promising...