Increased Conformational Flexibility of a Macrocycle–Receptor Complex Contributes to Reduced Dissociation Rates

Adrian Glas, Eike Christian Wamhoff, Dennis M. Krüger, Christoph Rademacher*, Tom N. Grossmann

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


Constraining a peptide in its bioactive conformation by macrocyclization represents a powerful strategy to design modulators of challenging biomolecular targets. This holds particularly true for the development of inhibitors of protein-protein interactions which often involve interfaces lacking defined binding pockets. Such flat surfaces are demanding targets for traditional small molecules rendering macrocyclic peptides promising scaffolds for novel therapeutics. However, the contribution of peptide dynamics to binding kinetics is barely understood which impedes the design process. Herein, we report unexpected trends in the binding kinetics of two closely related macrocyclic peptides that bind their receptor protein with high affinity. Isothermal titration calorimetry, 19F NMR experiments and molecular dynamics simulations reveal that increased conformational flexibility of the macrocycle–receptor complex reduces dissociation rates and contributes to complex stability. This observation has impact on macrocycle design strategies that have so far mainly focused on the stabilization of bioactive ligand conformations.

Original languageEnglish
Pages (from-to)16157-16161
Number of pages5
JournalChemistry - A European Journal
Issue number64
Publication statusPublished - 16 Nov 2017


This work was supported by the German Research Foundation (DFG, Emmy Noether program RA1944/2-1 and GR3592/2-1) and the European Research Council (ERC starting grant, no. 678623). We are also grateful for support by AstraZeneca, Bayer CropScience, Bayer HealthCare, Boehringer Ingelheim, Merck KGaA, and the Max Planck Society.

FundersFunder number
Boehringer Ingelheim
Bayer CropScience
Merck KGaA
Horizon 2020 Framework Programme678623
European Research Council
Bayer HealthCare
Deutsche ForschungsgemeinschaftGR3592/2-1, RA1944/2-1


    • F NMR spectroscopy
    • binding kinetics
    • cyclic peptides
    • molecular dynamics simulation
    • peptidomimetics


    Dive into the research topics of 'Increased Conformational Flexibility of a Macrocycle–Receptor Complex Contributes to Reduced Dissociation Rates'. Together they form a unique fingerprint.

    Cite this