Interaction of Zwitterionic Osmolyte Trimethylamine N-oxide (TMAO) with Molecular Hydrophobes: An Interplay of Hydrophobic and Electrostatic Interactions

Interaction of trimethylamine N -oxide (TMAO) with charged/uncharged moieties of proteins and lipids is an important elementary step toward the multifaceted biofunctions of TMAO. Using minimum area Raman difference spectroscopy (MA-RDS) of aqueous TMAO (1.0 M) in the presence of deuterated molecular hydrophobes (e.g., deuterated tetramethylammonium cation ( d- TMA + ) and tert- butylalcohol ( d -TBA)), we show that TMAO exhibits two distinct motifs of interaction with the cationic ( d- TMA + ) and uncharged ( d- TBA) hydrophobes. Specifically, the trimethylammonium moiety of TMAO undergoes van der Waals attraction with the tert -butyl group of d -TBA, which is governed by their mutual hydrophobic interaction with water. This makes their methyl groups less exposed to water. In contrast, for the cationic hydrophobe ( d- TMA + ), TMAO interacts electrostatically via its negatively charged-oxygen, which in turn orients the TMAO-methyls away from the hydrophobe ( d- TMA + ), keeping them exposed to water.