Small organic solutes in cells have various effects on proteins. For example, trimethylamine N-oxide (TMAO), which consists of N+O- and methyl (CH3–) 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 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. The biophysical chemistry and solution dynamics of aqueous TMAO solutions have been extensively investigated from experimentalviewpoints. Ab initio molecular dynamics (AIMD) simulations are essential for explaining the experimental results precisely and designing the osmotic pressure regulation ability artificially. Although there have been several sub-picosecond-order Born-Oppenheimer AIMD simulations with the density functional theory, previous studies have not revealed the intermolecular interaction, which is physicochemical origin of the molecular functions. The object of this study is to clarify the temporal evolution of intermolecular interactions in TMAO aqueous solution with a realistic condition of concentration. For this purpose, we applied the ab initio effective fragment potential - molecular dynamics simulation (EFP-MD), which is particularly suited to performing nanosecond-order AIMD simulations for systems containing several thousand atoms, for dilute aqueous TMAO solutions (0.18 mol L-1). For comparison, a dilute aqueous solution of tert-butyl alcohol (TBA), which is known as a protein denaturant, was also investigated.

Electronic fluctuation of trimethylamine N-oxide and tert-butyl alcohol in water: An effective fragment potential – molecular dynamics study

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