A prevalent intraresidue hydrogen bond stabilizes proteins

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Current protein structure prediction and design methods are limited by an incomplete understanding of protein folding interactions.
• Existing models may not fully account for all forces contributing to protein stability and conformation.

Purpose of the Study:

• To identify and characterize previously unappreciated hydrogen bonds within proteins.
• To investigate the role of these novel interactions in protein folding, stability, and disease.

Main Methods:

• Quantum chemical calculations
• Infrared spectroscopy
• Nuclear magnetic resonance (NMR) spectroscopy
• Biophysical analyses of synthetic β-sheets

Main Results:

• Demonstrated the existence of intramolecular hydrogen bonds between the amide proton and carbonyl oxygen of the same residue (C5 hydrogen bonds).
• Confirmed that C5 hydrogen bonds share characteristics with canonical hydrogen bonds.
• Showed that modulating C5 hydrogen bonds impacts the stability of β-sheets.
• Found C5 interactions are prevalent, present in ~5% of residues and ~94% of proteins, contributing significant conformational stability.
• Identified C5 hydrogen bonds as particularly stabilizing for amyloid β-sheets implicated in neurodegenerative diseases.

Conclusions:

• C5 hydrogen bonds are a significant, previously overlooked factor in protein structure and stability.
• These interactions play a critical role in stabilizing protein conformations, including those relevant to diseases like Alzheimer's.
• Incorporating C5 hydrogen bonds into computational force fields will enhance protein folding and dysfunction models.