The effects of urea, tetramethyl urea (TMU), and trimethylamine N-oxide (TMAO) on the structure and dynamics of aqueous solutions are studied using molecular dynamics simulations. It was found that urea has little effects on the water-water hydrogen-bond length and angle distributions except that it induces a slight collapse of the second shell in the hydrogen-bonding network. TMU and TMAO both strengthen the individual hydrogen bonds and significantly slow the orientational relaxation of water, but have opposite effects on the second shell structure of the hydrogen-bonding network: TMU distorts while TMAO enhances the tetrahedral water structure. Furthermore, TMAO significantly weakens the interactions between the amide carbonyl group and the water molecules, while TMU and urea both strengthen these interactions, with the effect of urea being much less significant than that of TMU. These conclusions are supported by molecular dynamics simulations of three different systems: a model amide compound CH(3)-NH-CO-CH(3) (NMA), and two polypeptides, GB1 and ELP. Consistent with earlier studies, we also found that urea interacts strongly with the carbonyl group through direct hydrogen bonding. The simulations for the denaturation of the polypeptide GB1 in urea solutions showed that the breaking of its native hydrogen bonds follows a step-by-step process and each step is strongly coupled to the formation of water-carbonyl hydrogen bonds, and to a less extent to the urea-carbonyl hydrogen-bond formation. Our simulation results reveal the potential importance of the indirect effects of cosolvents in protein denaturation or structure protection, particularly through modifying of the water-amide interactions.