Iterative coupling of 2-aminoisobutyric acid (Aib) has been achieved rapidly and efficiently using automated solid-phase peptide synthesis, employing diisopropylcarbodiimide (DIC) in the presence of ethyl cyanohydroxyiminoacetate (Oxyma). This method has...

Quaternary amino acids are important tools for the modification and stabilisation of peptide secondary structures. Here we describe a practical and scalable synthesis applicable to quaternary alpha-arylated amino acids (Q4As),...

Miniproteins reduce the complexity of the protein-folding problem allowing systematic studies of contributions to protein folding and stabilization. Here, we describe the rational redesign of a miniprotein, PP, comprising a polyproline-II helix, loop and  helix. The redesign provides a de novo framework to interrogate non-covalent interactions. Optimized PP has significantly improved thermal stability with a midpoint unfolding temperature (TM) of 51C. Its NMR structure indicates a higher density of stabilizing noncovalent interactions than the parent peptide, specifically increased CH-π interactions. In part, we attribute this to improved long-range electrostatic interactions between the two helical elements. We probe further sequence-to-stability relationships in the miniprotein through a series of rational mutations.