Halogen bonds between ligands and proteins: Can we use them in validation?

Area of Science:

• Structural biology
• Biochemistry
• Medicinal chemistry

Background:

• Halogen bonds are crucial non-covalent interactions in molecular recognition.
• Their role in drug development is significant, yet often underestimated in structural analyses.
• Standard validation protocols may not adequately assess halogen bond geometry.

Purpose of the Study:

• To analyze halogen bond geometry in ligand-protein complexes.
• To develop a quantitative score (HalBS) for evaluating halogen bond quality.
• To improve the analysis and validation of macromolecular structure models.

Main Methods:

• Analysis of halogen bonds in PDB-REDO database structures.
• Definition of key geometric parameters: donor-acceptor distance, bond angles (θ1, θ2).
• Development of the HalBS score based on geometric parameter distributions.

Main Results:

• Key geometric parameters for interatomic and halogen-π interactions were defined.
• The HalBS score effectively distinguishes between preferred, allowed, and outlier halogen bond geometries.
• A reference implementation of HalBS is available in PDB-REDO and as open-source code.

Conclusions:

• HalBS provides a valuable tool for assessing halogen bond quality in structural models.
• Improved treatment of halogen bonds enhances the reliability of ligand-protein complex analysis.
• This work is a foundational step towards better integration of halogen bond analysis in structural biology.