In cells, biological molecules function in an aqueous solution. Electrolytes and other small molecules play important roles in keeping the osmotic pressure of the cellular environment as well as the structure formation and function of biomolecules. More than a century ago Franz Hofmeister ranked the ions based on their salting-out ability on proteins. The series named after him was later found to be valid in salt effects on many other properties. The anionic Hofmeister series is generally written as CO32- > SO42-> F- > Cl- > Br- > I- ~ NO3-, with the ions on the left hand side called kosmotropes and those on the right hand side chaotropes.
A simple theory was formulated for salt effects on water/air surface tension, which takes into account the interactions of individual ions with water. The theory was then extended to understand how salts and other small molecules affect protein backbone solvation and protein secondary structure formation, with ion binding to the amide and ion pairing included. The theory predicts that at low concentrations co-solutes rich in proton donors and those rich in proton acceptors have opposite effects and function as protein secondary structure denaturants and renaturants, respectively, consistent with experimental observations: Urea and Gdm+, two common denaturants, are both rich in hydrogen donors, and the increase of amide solvation by the denaturants again can be a result of both direct and indirect effects, the latter increases the free hydrogen bond donors of water. In contrast, addition of molecules acting mainly as hydrogen acceptors, such as alcohols, GB, and TMAO desolvate the protein backbone and therefore enhance the secondary structure. MD simulations used to test these theoretical results will also be discussed.