Secondary Binding Interactions in a Synthetic Receptor for Trimethyllysine.

Area of Science:

• Chemical biology
• Molecular recognition
• Supramolecular chemistry

Background:

• Synthetic receptors are crucial for understanding molecular recognition.
• Trimethyllysine (Kme3) is a post-translational modification with implications in epigenetics.
• A2 N is a synthetic receptor designed for Kme3 recognition.

Purpose of the Study:

• To investigate the impact of neighboring lysine (Lys) and arginine (Arg) residues on the binding affinity and selectivity of the synthetic receptor A2 N for trimethyllysine (Kme3).
• To elucidate the thermodynamic mechanisms underlying the enhanced binding interactions.

Main Methods:

• Systematic study of secondary interactions using isothermal titration calorimetry (ITC).
• Variation of spacing between KmeX (X=0, 3) and ancillary Lys or Arg residues.
• Analysis of binding thermodynamics (enthalpy and entropy) to differentiate interaction mechanisms.

Main Results:

• Both neighboring Lys and Arg residues enhance A2 N binding to Kme3 by approximately 1 kcal/mol.
• The spacing between KmeX and the ancillary residues has minimal impact on binding improvement.
• Arginine-mediated binding enhancement is enthalpically driven, while lysine-mediated enhancement is entropically driven.

Conclusions:

• Neighboring Lys and Arg residues significantly improve the binding of synthetic receptor A2 N to trimethyllysine.
• The distinct thermodynamic profiles suggest different interaction modes for Lys and Arg at the secondary binding site.
• These findings offer insights into designing more selective and potent synthetic receptors through strategic placement of amino acid residues.