Bioinformatics leading to conveniently accessible, helix enforcing, bicyclic ASX motif mimics (BAMMs)

Helix mimicry provides probes to perturb protein-protein interactions (PPIs). Helical conformations can be stabilized by joining side chains of non-terminal residues ( stapling ) or via capping fragments. Nature exclusively uses capping, but synthetic helical mimics are heavily biased towards stapling. This study comprises: (i) creation of a searchable database of unique helical N -caps (ASX motifs, a protein structural motif with two intramolecular hydrogen-bonds between aspartic acid/asparagine and following residues); (ii) testing trends observed in this database using linear peptides comprising only canonical L-amino acids; and, (iii) novel synthetic N -caps for helical interface mimicry. Here we show many natural ASX motifs comprise hydrophobic triangles , validate their effect in linear peptides, and further develop a biomimetic of them, B icyclic A SX M otif M imics (BAMMs). BAMMs are powerful helix inducing motifs. They are synthetically accessible, and potentially useful to a broad section of the community studying disruption of PPIs using secondary structure mimics.