Halogen bonds as orthogonal molecular interactions to hydrogen bonds

Area of Science:

• Biochemistry
• Chemical Physics
• Structural Biology

Background:

• Hydrogen bonds (H-bonds) are crucial for protein structure and function.
• Halogen bonds (X-bonds) are emerging as important non-covalent interactions.
• The interplay between H-bonds and X-bonds at shared acceptors is not well understood.

Purpose of the Study:

• To investigate the geometric and energetic relationship between H-bonds and X-bonds.
• To understand how peptide conformation influences these interactions.
• To explore the potential for designing halogenated molecules based on these principles.

Main Methods:

• Computational analysis of electrostatic potentials on oxygen acceptors.
• Analysis of protein data to observe H-bond and X-bond patterns.
• Geometric and energetic assessments of orthogonal interactions.

Main Results:

• X-bonds are geometrically perpendicular to H-bonds at common carbonyl oxygen acceptors.
• This orthogonality arises from the differential population of oxygen's electronegative potentials.
• Protein conformation dictates H-bond geometry, influencing X-bond accessibility.

Conclusions:

• A strong preference for orthogonal H- and X-bond geometry exists.
• X-bond geometry can be predicted from H-bond patterns in proteins.
• This principle enables rational design of halogenated ligands for drug development and biomolecular engineering.