What is the hydrophobic interaction contribution to the stabilization of micro-hydrated complexes of trimethylamine oxide (TMAO)? A joint DFT-D, QTAIM, and MESP study.

Micro-hydrated trimethylamine oxide (TMAO) has been investigated using a range-separated-hybrid functional including empirical dispersion correction. Electrophilic and nucleophilic sites on TMAO and water clusters have been identified using the molecular electrostatic potential (MESP). The nature of the chemical bonding in the different isomers of the micro-hydrated complexes has been investigated with the topological analysis of the electron density (QTAIM) method. For complexes containing one to four water molecules, the strongest intermolecular interactions consist in hydrogen bonding between the oxygen atom of the TMAO and hydrogen atoms of water molecules. From five water molecules, interactions between water molecules become the main source of stabilization of the most stable isomer. From four stationary points corresponding to the 1:1 (TMAO:HO) complex, we determined the minimum distances between water molecules and central TMAO allowing the latter molecule to be encapsulated within a water clathrate-type cage. Optimization of TMAO encapsulated within two water cages (5 and 56) suggests that only in the case of the 5 6 water cage the insertion of TMAO, the preservation of the hydrogen bonding between water molecules is energetically favorable. The interaction energy between one inserted TMAO and the 5 6 water cage was calculated to be around 150 kJ/mol with respect to the ground state of two partners. This result suggests that a thorough investigation of mono-hydrated complexes may be particularly relevant to identify the most suitable water cage for encapsulating a given solute.