Experimental and Computational Models for Side Chain Discrimination in Peptide–Protein Interactions

Anna Lidskog, Sami Dawaigher, Carlos Solano Arribas, Anna Ryberg, Jacob Jensen, Karl Erik Bergquist, Anders Sundin, Per Ola Norrby, Kenneth Wärnmark

Research output: Contribution to journalArticlepeer-review


A bis(18-crown-6) Tröger's base receptor and 4-substituted hepta-1,7-diyl bisammonium salt ligands have been used as a model system to study the interactions between non-polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an all-anti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor-ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl- and a phenyl group to an aromatic cavity, via CH-π, and combined aromatic CH-π and π-π interactions to be −1.7 and −3.3 kJ mol−1, respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior.

Original languageEnglish
Pages (from-to)10883-10897
Number of pages15
JournalChemistry - A European Journal
Issue number42
Publication statusPublished - 2021 Jul 26

Subject classification (UKÄ)

  • Analytical Chemistry

Free keywords

  • computational chemistry
  • host–guest systems
  • NMR spectroscopy
  • NMR titrations
  • peptide-protein interactions


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