Hidden Route of Protein Damage via Confined Oxygen

Abstract

Oxidative modifications are known to disrupt protein folding and function, and are strongly implicated in aging and various human diseases. Conventional oxidation pathways typically rely on the free diffusion of reactive oxygen species (ROS), which predominantly attack the protein surface. However, it remains unclear whether and how internal protein folds capable of transiently trapping molecular oxygen (O2) contribute to oxidative damage. In this talk, I will present our recent discovery of a previously unrecognized pathway of protein damage—termed O2-confined photooxidation—uncovered through a multidisciplinary approach combining single-molecule magnetic tweezers, molecular dynamics simulations, density functional theory calculations, and electron paramagnetic resonance spectroscopy [1]. In this mechanism, O2 is first captured within internal protein cavities and subsequently converted into multiple ROS species, primarily mediated by tryptophan residues under blue light irradiation. These ROS then diffuse in a spatially constrained manner to attack the protein interior, resulting in localized structural damage. This confined photooxidative process appears to have widespread implications, affecting a broad range of cellular proteins, as supported by whole-cell proteomic analysis. Our findings suggest that the O2-confined photooxidation may represent a latent protein damage pathway, particularly in human tissues exposed to visible light, such as the skin and eyes.