Fluorine bonding--how does it work in protein-ligand interactions?

Area of Science:

• Computational chemistry
• Structural biology
• Medicinal chemistry

Background:

• Fluorination is a common strategy in drug design to enhance metabolic stability and membrane permeability.
• The role of fluorine atoms in protein-ligand interactions, known as fluorine bonding, is a recently recognized phenomenon.

Purpose of the Study:

• To systematically investigate the geometric and energetic characteristics of fluorine bonding.
• To assess the contribution of fluorine bonding to protein-ligand binding affinity.
• To evaluate the performance of various computational methods in reproducing fluorine bonding energies.

Main Methods:

• Combined X-ray structural analysis and theoretical calculations (ONIOM-based QM/MM) to study fluorine bonding.
• Systematic investigation of geometric and energetic properties of fluorine-protein-ligand interactions.
• Performance evaluation of 14 quantum mechanics (QM) and molecular mechanics (MM) methods against high-level theoretical calculations (MP2/aug-cc-pVDZ).

Main Results:

• Short contacts involving fluorine atoms (generalized fluorine bonding) are frequently observed in protein-fluorinated ligand complexes.
• Fluorine bonding exhibits characteristics similar to sulfur-involved hydrogen bonding and differs from conventional hydrogen/halogen bonding.
• Fluorine bonding contributes to protein-ligand binding, although individual fluorine bonds have modest strength.
• Most QM methods and few MM methods accurately reproduce calculated fluorine bonding energies.
• MPWLYP functional and MMFF94 force field are recommended for studying moderate and large fluorine bonding systems, respectively.

Conclusions:

• Fluorine bonding is a significant interaction in protein-ligand systems, influencing binding affinity.
• The study provides recommendations for computational methods to accurately model fluorine bonding.
• Understanding fluorine bonding is crucial for rational drug design and development of novel therapeutic agents.