The structural and energetic properties of solutions containing water, urea, and trimethylamine-N-oxide (TMAO) are examined using molecular dynamics simulations. Such systems are of interest mainly because TMAO acts to counter the protein denaturing effect of urea. Even at relatively high concentration, TMAO is found to fit well into the urea-water structure. The underlying solution structure is influenced by TMAO, but these perturbations tend to be modest. The TMAO-water and TMAO-urea interaction energies make an important contribution to the total energy in solutions where counter-denaturing effects are expected. TMAO-water and TMAO-urea hydrogen bonds have the largest hydrogen-bond energies in the system. Additionally, TMAO cannot hydrogen bond with itself, and hence it interacts strongly with water and urea. These observations suggest that the mechanism of TMAO counter denaturation is simply that water and urea prefer to solvate TMAO rather than the protein, hence inhibiting its unfolding.

In dilute aqueous solution, tert-butyl alcohol (TBA) tends to aggregate but trimethylamine-N-oxide (TMAO) does not. Given that both molecules have very similar geometry with hydrophobic and hydrophilic groups, it is interesting to ask why they behave so differently in aqueous solution. To explore this question, we use molecular dynamics simulations to study two models representing TBA and TMAO that differ essentially only in their electrostatic properties. It is shown that this difference is sufficient to give the different solution behavior. Furthermore, the principal difference identified is that the hydrophilic group of TMAO (the oxygen) interacts on average much more strongly with water than the corresponding group (the hydroxyl) of TBA. A hydrogen-bond analysis shows that water-TBA and water-TMAO hydrogen bonds are similar in number, but that the hydrogen-bond energy is much more negative for water-TMAO. In all likelihood, this accounts for the different behavior in dilute aqueous solution.

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Molecular dynamics simulations are used to obtain potentials of mean force for pairs of neopentane molecules immersed in aqueous solutions containing urea, trimethylamine-N-oxide (TMAO), or both solutes at once. It is shown that the hydrophobic attraction acting between neopentane pairs in pure water and in water-urea solution is completely destroyed by the addition of TMAO. This strongly suggests that TMAO does not counter the protein denaturing effect of urea by enhancing hydrophobic attraction amongst nonpolar groups.

The hydrogen bonded structure and dynamics of liquid-vapor interfaces of aqueous methanol solutions of varying compositions are investigated by means of molecular dynamics simulations. The dynamical aspects of the interfaces are investigated in terms of the single-particle dynamical properties such as the relaxation of velocity autocorrelation and the translational diffusion coefficients along the perpendicular and parallel directions and the dipole orientational relaxation of the interfacial water and methanol molecules and also in terms of the relaxation of water-water, water-methanol, and methanol-methanol hydrogen bonds at interfaces at 298 K. The results of the interfacial dynamics are compared with those of the corresponding bulk phases. The inhomogeneous density, anisotropic orientational profiles, surface tension, and the pattern of hydrogen bonding are calculated in order to characterize the location, width, microscopic structure, and the thermodynamic aspects of the interfaces and to explore their effects on the interfacial dynamical properties of water and methanol molecules.