Molecular tweezers with varying anions: a comparative study

Area of Science:

• Biochemistry
• Molecular Biology
• Medicinal Chemistry

Background:

• Molecular tweezers are investigated for their potential to modulate protein aggregation implicated in neurodegenerative diseases like Alzheimer's and Parkinson's.
• Selective binding to protein lysine residues is a proposed mechanism for tweezer activity.

Purpose of the Study:

• To systematically investigate the binding of four water-soluble molecular tweezers (1a-d) to amino acids and peptides containing lysine or arginine residues.
• To elucidate the binding modes and forces governing host-guest interactions between tweezers and amino acid/peptide targets.
• To provide a foundation for understanding the influence of tweezers on protein aggregation and enzyme activity.

Main Methods:

• Fluorescence spectroscopy
• Nuclear Magnetic Resonance (NMR) spectroscopy
• Isothermal Titration Calorimetry (ITC)
• Quantum Mechanics/Molecular Mechanics (QM/MM) calculations
• Ab initio (1)H NMR shift calculations

Main Results:

• Tweezers 1a-c demonstrated threading of lysine or arginine side chains through the tweezer cavity.
• Tweezer 1d showed preferential positioning of the guest molecule outside the cavity.
• Key binding forces identified include ionic, CH-π, and hydrophobic interactions.
• Experimental and theoretical data were compared to validate binding modes.

Conclusions:

• The study provides clear evidence for distinct binding modes of molecular tweezers to amino acids and peptides.
• Understanding these host-guest interactions is crucial for developing tweezers as therapeutic agents for protein aggregation disorders.
• The findings offer deep insights into molecular tweezer mechanisms relevant to enzyme inhibition and protein aggregation.