Universal cold RNA phase transitions

RNA’s diversity of structures and functions impacts all life forms since primordia. We use calorimetric force spectroscopy to investigate RNA folding landscapes in previously unexplored low-temperature conditions. We find that Watson–Crick RNA hairpins, the most basic secondary structure elements, undergo a glass-like transition below T G ∼ 20 ° C where the heat capacity abruptly changes and the RNA folds into a diversity of misfolded structures. We hypothesize that an altered RNA biochemistry, determined by sequence-independent ribose–water interactions, outweighs sequence-dependent base pairing. The ubiquitous ribose–water interactions lead to universal RNA phase transitions below T G , such as maximum stability at T S ∼ 5 ° C where water density is maximum, and cold denaturation at T C ∼ − 50 ° C. RNA cold biochemistry may have a profound impact on RNA function and evolution.