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

Interaction of trimethylamine -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 (TMA) and butylalcohol (-TBA)), we show that TMAO exhibits two distinct motifs of interaction with the cationic (TMA) and uncharged (TBA) hydrophobes. Specifically, the trimethylammonium moiety of TMAO undergoes van der Waals attraction with the -butyl group of -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 (TMA), TMAO interacts electrostatically via its negatively charged-oxygen, which in turn orients the TMAO-methyls away from the hydrophobe (TMA), keeping them exposed to water.