Newly identified C-H⋯O hydrogen bond in histidine

Area of Science:

• Biochemistry
• Structural Biology
• Chemical Physics

Background:

• Histidine residues play critical roles in protein structure and function.
• Hydrogen bonding is a key interaction in stabilizing protein conformations.
• Previous studies identified Cε-H bonds in histidine hydrogen bonding, but Cδ-H interactions were less explored.

Purpose of the Study:

• To identify and characterize novel Cδ-H⋯O histidine hydrogen bonding interactions in proteins.
• To computationally investigate the properties of these hydrogen bonds using model systems.
• To elucidate the significance of Cδ-H⋯O interactions in protein structure and function.

Main Methods:

• Neutron diffraction to identify hydrogen bond motifs in protein crystal structures.
• Computational chemistry (using 5-methylimidazole and 5-methylimidazolium models) to characterize hydrogen bond strengths and properties.
• Analysis of IUPAC criteria for hydrogen bonding.

Main Results:

• Identification of multiple Cδ-H⋯O hydrogen bonding interactions involving histidine side chains in various proteins, including in β-sheets and with water molecules.
• Experimental and computational evidence confirms Cδ-H⋯O and Cε-H⋯O interactions meet IUPAC criteria.
• Cδ-H⋯O interactions in the τ-tautomer are approximately twice as strong as in the π-tautomer.
• Protonated histidinium forms significantly stronger complexes than neutral histidine tautomers.
• Formation of one hydrogen bond minimally affects the imidazole ring's capacity for further interactions.

Conclusions:

• The Cδ-H⋯O interaction is a significant, previously underappreciated hydrogen bonding motif in proteins.
• These interactions contribute to β-sheet stability, protein conformation, solvent interactions, and active site mechanisms.
• Recognizing the polarity and hydrogen bonding capacity of histidine C-H bonds can enhance molecular modeling and deepen understanding of histidine's diverse roles.