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

A bis(18-crown-6) Troger'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-pi, and combined aromatic CH-pi and pi-pi 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.

Automated summary

In this study, a model system involving a bis(18-crown-6) Troger's base receptor and 4-substituted hepta-1,7-diyl bisammonium salt ligands was used to investigate interactions between non-polar peptides side chains and a protein's aromatic cavity. Experimental results showed a preference for an all-anti conformation of the heptane chain in most ligands, with the substituent located inside or partially inside the aromatic cavity when bound to the receptor. Computational analysis revealed that molecular mechanics (MM) methods outperformed density functional theory (DFT) methods in estimating free binding energies.