Elucidating the interactions of cosolvents and cosolutes, for example, urea and inorganic salts, with proteins plays a very important role in understanding protein structure formation, solubility, and dynamics. In a recent study, we rationalized the experimentally observed salt effects on water/air surface tension and showed the potential importance of cation/anion association/cooperativity. In this paper, we focus on salt effects on the solvation of simple model compounds such as peptides and benzene, hoping to obtain a more general and simple understanding of the Hofmeister series. We show here that preferred cation binding to the carbonyl and anion to the apolar surface of model polypeptides can help explain the experimentally observed salt effects on polypeptide activity coefficient in water. The effects of ions on the solvation of amide group can be both direct and indirect, which together attribute to an effective change of the proton donor/acceptor equilibrium in aqueous solutions. We show that such an argument can be used to understand not only the salt effects on solubility of amides but also why some organic compounds are protein secondary structure denaturants whereas others are protectants.