Are Protein Cavities and Pockets Commonly Used by Redox Active Signalling Molecules?

Abstract

It has been well known for a long time that inert gases, such as xenon (Xe), have significant biological effects. As these atoms are extremely unlikely to partake in direct chemical reactions with biomolecules such as proteins, lipids, and nucleic acids, there must be some other mode of action to account for the effects reported. It has been shown that the topology of proteins allows for cavities and hydrophobic pockets, and it is via an interaction with such protein structures that inert gases are thought to have their action. Recently, it has been mooted that the relatively inert gas molecular hydrogen (H2) may also have its effects via such a mechanism, influencing protein structures and actions. H2 is thought to also act via interaction with redox active compounds, particularly the hydroxyl radical (·OH) and peroxynitrite (ONOO−), but not nitric oxide (NO·), superoxide anions (O2·−) or hydrogen peroxide (H2O2). However, instead of having a direct interaction with H2, is there any evidence that these redox compounds can also interact with Xe pockets and cavities in proteins, either having an independent effect on proteins or interfering with the action of inert gases? This suggestion will be explored here.

Red Blood Cell Storage with Xenon: Safe or Disruption?

“…Despite the chemical inertness of xenon, there is evidence of its biological activity [ 59 ]. On the one hand, the unique properties of xenon allow it to diffuse and interact with cellular structures at the molecular level.…”

“…On the other hand, xenon is believed to be able to interact with proteins that have complex structures and contain various cavities and microsites. These microsites are known as “xenon-binding pockets” [ 59 , 60 , 61 , 62 ]. Interestingly, this interaction is not static, and these pockets are not occupied by xenon alone.…”

An Interplay of Gases: Oxygen and Hydrogen in Biological Systems

“…Globin proteins are a model system, where several inert gases are known to interact [47,48] H 2 and O 2 interacting May account for some of the effects seen? Discussed here…”

“…Such features are typically lined with amino acids of leucine, isoleucine, alanine or valine, characteristically formed in proteins over 100 amino acids in length (reviewed by Roose et al [74]). Hydrophobic pockets enable non-covalent/van der Waals interactions with noble gases such as argon (Ar), krypton (Kr), the much larger atom, xenon (Xe) [75], and perhaps molecular hydrogen [48]. Research conducted using X-ray crystallography on one of the largest noble gases, Xe, reports that hydrophobicity and the volume of gas delivered are the primary factors in determining gas-protein binding, occurring via weak London dispersion forces [76].…”

“…However, H 2 is not dissimilar to He, which was suggested to be a therapeutic gas almost 100 years ago [93] and has since been studied for its biological effects [94]. Therefore, this mode of action of H 2 would no doubt be worthy of further investigation, as it would for a range of small-some gaseous-signalling molecules [48]. If such gases as H 2 are interacting with hydrophobic pockets in proteins such as haemoglobin and myoglobin-the model proteins for studying such effects-is this affecting O 2 transport in animals?…”