Rapid Rational Design of Cyclic Peptides Mimicking Protein–Protein Interfaces

The cPEPmatch approach is a rapid computational methodology for the rational design of cyclic peptides to target desired regions of protein–protein interfaces. The method selects cyclic peptides that structurally match backbone structures of short segments at a protein–protein interface. In a second step, the cyclic peptides act as templates for designed binders by adapting the amino acid side chains to the side chains found in the target complex. A link to access the different tools that comprise the cPEPmatch method and a detailed step-by-step guide is provided. We outline the protocol by following the application to a trypsin protease in complex with the bovine inhibitor protein (BPTI). An extension of our original approach is also presented, where we give a detailed description of the usage of the cPEPmatch methodology focusing on identifying hot regions of protein–protein interfaces prior to the matching. This extension allows one to reduce the amount of evaluated putative cyclic peptides and to specifically design only those that compete with the strongest protein–protein binding regions. It is illustrated by an application to an MHC class I protein complex.