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Rapid Rational Design of Cyclic Peptides Mimicking Protein–Protein Interfaces

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Part of the Methods in Molecular Biology book series (MIMB,volume 2405)


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.

Key words

  • Protein–protein interactions
  • Protein interaction inhibition
  • Protein binding modulation
  • Peptidomimetics
  • Cyclic peptide design
  • Drug design with cyclic peptides
  • Rational cyclic peptide binders

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This research was conducted within the Max Planck School Matter to Life supported by the German Federal Ministry of Education and Research (BMBF) in collaboration with the Max Planck Society. We acknowledge also support by the Leibniz super computer (LRZ) center for providing supercomputer support by grant pr27za.

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Correspondence to Martin Zacharias .

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Santini, B.L., Zacharias, M. (2022). Rapid Rational Design of Cyclic Peptides Mimicking Protein–Protein Interfaces. In: Simonson, T. (eds) Computational Peptide Science. Methods in Molecular Biology, vol 2405. Humana, New York, NY.

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1854-7

  • Online ISBN: 978-1-0716-1855-4

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