Proteins are among the most studied molecules in biology, yet new research from the University of Göttingen shows they can still hold surprising secrets. Researchers have discovered previously undetected chemical bonds within archived protein structures, revealing an unexpected complexity in protein chemistry.

These newly identified nitrogen-oxygen-sulfur (NOS) linkages broaden our understanding of how proteins respond to oxidative stress, a condition where harmful oxygen-based molecules build up and can damage proteins, DNA, and other essential parts of the cell. The new findings are published in Communications Chemistry.

The research team systematically re-analyzed over 86,000 high-resolution protein structures from the Protein Data Bank, a global public repository of protein structures, using a new algorithm that they developed inhouse called SimplifiedBondfinder. This pipeline combines machine learning, quantum mechanical modeling, and structural refinement methods to reveal subtle chemical bonds that were missed by conventional analyses.

Unexpectedly, NOS linkages were not restricted to previously known amino acid pairs but were also discovered between the amino acid pairs arginine-cysteine and glycine-cysteine. NOS linkages were first discovered by research led by Professor Kai Tittmann at Göttingen University.

“Our work shows that the Protein Data Bank still holds hidden chemistry,” said Dr. Sophia Bazzi at Göttingen University’s Institute of Physical Chemistry, who led the study. “By developing new digital tools and revisiting existing data, we uncovered chemical interactions that had remained unnoticed for decades.”

These NOS bonds act as molecular switches, stabilizing proteins under oxidative stress and potentially influencing a whole range of biological processes. “Our approach has much wider implications,” Bazzi adds. “It can uncover overlooked chemical bonds, leading to improved protein models and advancing protein engineering, drug design, and synthetic biology.”