The intermolecular interactions of
noble gases in
biological systems are associated with numerous biochemical responses, including apoptosis,
inflammation,
anesthesia,
analgesia, and neuroprotection. The molecular modes of action underlying these responses are largely unknown. This is in large part due to the limited experimental techniques to study
protein-gas interactions. The few techniques that are amenable to such studies are relatively low-throughput and require large amounts of purified
proteins. Thus, they do not enable the large-scale analyses that are useful for
protein target discovery. Here, we report the application of stability of
proteins from rates of oxidation (SPROX) and limited proteolysis (LiP) methodologies to detect
protein-
xenon interactions on the proteomic scale using protein folding stability measurements. Over 5000
methionine-containing
peptides and over 5000 semi-tryptic
peptides, mapping to ∼1500 and ∼950
proteins, respectively, in the yeast
proteome, were assayed for Xe-interacting activity using the SPROX and LiP techniques. The SPROX and LiP analyses identified 31 and 60 Xe-interacting
proteins, respectively, none of which were previously known to bind Xe. A bioinformatics analysis of the proteomic results revealed that these Xe-interacting
proteins were enriched in those involved in
ATP-driven processes. A fraction of the
protein targets that were identified are tied to previously established modes of action related to
xenon's
anesthetic and organoprotective properties. These results enrich our knowledge and understanding of biologically relevant
xenon interactions. The sample preparation protocols and analytical methodologies developed here for
xenon are also generally applicable to the discovery of a wide range of other
protein-gas interactions in complex
biological mixtures, such as cell lysates.