Stapled peptide design: principles and roles of computation

Stapling is a key technique for stabilising peptides in an α-helical structure. The resultant stapled peptides are then able to compete efficiently for binding to protein targets involved in protein-protein interactions that are mediated by α-helices. Certain general design principles to optimise their binding and biological activity have emerged in recent years. This is accompanied by an increasing use of computational methods in stapled peptide design. In this article, we detail these design principles and review the contributions that computation has made to the field. We also highlight several pressing questions regarding the mechanism of action of stapled peptides, which could potentially be resolved by computational means.