Concentration dependence of dynamics and hydrogen bonding in aqueous solutions of urea, methyl-substituted ureas, and trimethylamine N-oxide.

[Display omitted] • Developed a consistent force field for urea and methyl-substituted ureas. • Reproduces unusual concentration dependent behavior of diffusion of tetramethylurea. • Shows cosolute diffusion is connected to bulk water diffusion via hydrogen bonds between their oxygen and water. • Indicates greater hydration of oxygen of trimethylamine N-oxide leads to stronger hydrogen bonding in the solution. Organic cosolutes can have profound effects on protein stability, and their behavior in aqueous solutions can provide a molecular understanding of these effects. Urea denatures proteins while methyl-substituted ureas are stronger denaturants and the similar cosolute trimethylamine N-oxide (TMAO) is a protein stabilizer. Here, differences between aqueous solutions of urea, dimethylurea (DMU), tetramethylurea (TMU), and TMAO are explored via molecular dynamics simulations. A consistent force field for urea and the methylureas is first developed that reproduces their experimental structure and dynamics in aqueous solution. Simulations show that the cosolutes generally diffuse more slowly with increasing concentration up to ∼ 4 M and that since the cosolutes are hydrogen bonded to water, bulk water also diffuses slower. However, the diffusion of TMU shows a dramatic increase at higher molar concentrations because due to the very small mole fraction of water in the TMU solutions so that it behaves more like pure liquid TMU. The cosolutes also generally diffuse more slowly with increasing size, although the diffusion of TMAO is even slower than DMU because of greater hydration of its oxygen. The slower diffusion of TMAO leads to larger viscosities, which further increases hydrogen bond lifetimes and leads to even slower diffusion in a feedback loop. Ultimately, this strengthens hydrogen bonds within TMAO solutions relative to urea and methylurea solutions. [ABSTRACT FROM AUTHOR]