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

Area of Science:

• Supramolecular Chemistry
• Computational Chemistry
• Structural Biology

Background:

• Understanding non-polar peptide side chain interactions with protein aromatic cavities is crucial for drug design and protein function studies.
• A model system using a bis(18-crown-6) Tröger's base receptor and bisammonium salt ligands was developed to investigate these interactions.

Purpose of the Study:

• To quantitatively and qualitatively analyze the discrimination of ligands by the Tröger's base receptor based on ligand substituents.
• To determine the preferred conformations of heptane chains in ligands, both free and bound.
• To estimate the binding free energies of methyl and phenyl groups within the aromatic cavity via CH-π and π-π interactions.

Main Methods:

• Nuclear Magnetic Resonance (NMR) titrations were employed for quantitative binding analysis.
• 2D NMR techniques (NOESY/ROESY) were utilized to determine ligand conformations and binding modes.
• Experimental data was used to evaluate the performance of computational methods like molecular mechanics (MM) and density functional theory (DFT).

Main Results:

• An all-anti conformation of the heptane chain was favored for most ligands, irrespective of receptor binding.
• Ligand substituents were consistently found within or partially within the receptor's aromatic cavity.
• Estimated free binding energies for methyl and phenyl groups were -1.7 kJ/mol (CH-π) and -3.3 kJ/mol (CH-π and π-π interactions), respectively.
• Molecular mechanics (MM) demonstrated superior accuracy compared to DFT in predicting experimental binding energies.

Conclusions:

• The Tröger's base receptor effectively discriminates ligands based on substituents, providing insights into peptide-protein binding.
• MM methods are reliable for modeling CH-π and π-π interactions in such systems.
• This study validates a model system for exploring non-polar interactions relevant to protein binding pockets.