Structure-based design of an aromatic helical foldamer-protein interface

Area of Science:

• Biochemistry
• Structural Biology
• Medicinal Chemistry

Background:

• Human carbonic anhydrase II (HCAII) is a validated drug target.
• Aromatic foldamers offer a scaffold for designing enzyme inhibitors.
• Controlling foldamer structure and protein interactions is key for drug development.

Purpose of the Study:

• To design and synthesize modified aromatic foldamers with enhanced interactions with HCAII.
• To investigate the impact of foldamer modifications on protein-ligand interface and helix handedness.
• To assess the binding affinity of modified foldamers to HCAII.

Main Methods:

• Solid-state structure determination of HCAII-foldamer complexes.
• Computational analysis of protein-ligand interactions.
• Molecular dynamics simulations.
• Solid-phase synthesis of novel foldamer sequences.
• RP-HPLC purification.
• Fluorescence competition assay for binding affinity (K_D) determination.

Main Results:

• Foldamer-protein interface was extended through predictable side-chain modifications.
• Side-chain alterations did not affect main-chain behavior, allowing independent implementation.
• Main-chain units derived from various aromatic δ-amino acids were interchangeable without altering helix curvature.
• Despite design improvements, binding affinity (K_D) to HCAII did not significantly improve.

Conclusions:

• Predictable modification of foldamer side chains can enhance protein interface interactions.
• Aromatic foldamer scaffolds allow for independent tuning of side-chain and main-chain properties.
• Further optimization is needed to translate improved structural interactions into enhanced binding affinity for HCAII inhibition.