Comprehensive computational design of ordered peptide macrocycles

Abstract

Macrocycles by design Macrocyclic peptides have diverse properties, including antibiotic and anticancer activities. This makes them good therapeutic leads, but screening libraries only cover a fraction of the sequence space available to peptides comprising D and L amino acids. Hosseinzadeh et al. achieved near-complete coverage in sampling the sequence space for 7- to 10-residue cyclic peptides and identified more than 200 designs predicted to fold into stable structures. Of 12 structures determined, nine were close to the computational models. They also sampled and designed 11- to 14-residue macrocycles, but without complete coverage. The designed macrocycles provide a path forward for engineering new therapeutics. Science , this issue p. 1461