Small organic solutes in cells have various effects on proteins. For example, trimethylamine N-oxide (TMAO, Figure ), which consists of N + O -and methyl (CH 3 -) groups, has been found in deep-sea fishes and is a known osmolyte that preserves the physiological functions of proteins. However, the preservation mechanism of the osmotic pressure is still under debate; the proposed explanations include an attractive direct interaction between TMAO and proteins 2 or indirect interactions via structural changes of an aqueous solution as a molecular aggregate. If the mechanism by which TMAO allows physiological functional preservation in proteins is clarified, it would make fundamental scientific contributions to, for example, the next generation of medicine by accelerating the development of artificial chaperones and understanding the mechanism of atherosclerosis. Therefore, it is necessary to understand the fundamental physical properties of TMAO.