The folding of proteins is usually studied in dilute aqueous solutions of controlled pH, but it has recently been demonstrated that reversible unfolding can occur in other media. Particular stability is conferred on the protein (folded or unfolded) when the process occurs in 'protic ionic liquids' (pILs) of controlled proton activity. This activity ('effective pH') is determined by the acid and base components of the pIL and is characterized in the present study by the proton chemical shift of the NH proton. Here we propose a 'refoldability' or 'refolding index' (RFI) metric for assessing the stability of folded biomolecules in different solvent media, and demarcate high RFI zones in hydrated pIL media using ribonuclease A and hen egg white lysozyme as examples. Then we show that, unexpectedly, the same high RFIs can be obtained in pIL media that are 90% inorganic in character (simple ammonium salts). This leads us to a conjecture related to the objections that have been raised to 'primordial soup' theories for biogenesis, objections that are based on the observation that all the bonds involved in biomacromolecule formation are hydrolyzed in ordinary aqueous solutions unless specifically protected. The ingredients for primitive ionic liquids (NH3, CO, HCN, CO2, and water) were abundant in the early earth atmosphere, and many experiments have shown how amino acids could form from them also. Cyclical concentration in evaporating inland seas could easily produce the type of ambient-temperature, non-hydrolyzing, media that we have demonstrated here may be hospitable to biomolecules, and that may be actually encouraging of biopolymer assembly. Thus a plausible variant of the conventional 'primordial soup' model of biogenesis is suggested.
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