DO as an Imperfect Replacement for HO: Problem or Opportunity for Protein Research?

DO is commonly used as a solvent instead of HO in spectroscopic studies of proteins, in particular, in infrared and nuclear-magnetic-resonance spectroscopy. DO is chemically equivalent to HO, and the differences, particularly in hydrogen-bond strength, are often ignored. However, replacing solvent water with DO can affect not only the kinetics but also the structure and stability of biomolecules. Recent experiments have shown that even the mesoscopic structures and the elastic properties of biomolecular assemblies, such as amyloids and protein networks, can be very different in DO and HO. We discuss these findings, which probably are just the tip of the iceberg, and which seem to call for obtaining a better understanding of the HO/DO-isotope effect on water-water and water-protein interactions. Such improved understanding may change the differences between HO and DO as biomolecular solvents from an elephant in the room to an opportunity for protein research.