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.