Halogen Bonding: An Underestimated Player in Membrane-Ligand Interactions.

Area of Science:

• Biochemistry
• Computational Chemistry
• Pharmacology

Background:

• Halogen bonds (XBs) are noncovalent interactions involving electrophilic halogen atoms.
• XBs are increasingly utilized in drug discovery for modulating protein-ligand interactions.
• Their role in biological membrane systems has not been well-established.

Purpose of the Study:

• To provide direct evidence for halogen bonds within biological membrane systems.
• To investigate the influence of XBs on halogenated compound interactions with phospholipids.
• To explore the role of XBs in membrane insertion and partitioning of ligands.

Main Methods:

• Molecular dynamics simulations were employed to model interactions.
• Halobenzene derivatives and a model phospholipid bilayer were used.
• Analysis focused on favorable interactions between ligands and membrane components.

Main Results:

• Direct evidence for halogen bonds between halobenzene derivatives and phospholipid acceptors (phosphate/ester oxygens) was found.
• XB-mediated recognition influences ligand membrane insertion profiles and orientation.
• XBs were systematically observed during the water-to-membrane insertion process.

Conclusions:

• Halogen bonds play a significant role in biological membrane systems, previously overlooked.
• XB interactions impact the pharmacological and toxicological profiles of halogenated compounds.
• Halogen bonds should be incorporated into membrane partition models for drug development.