Co-solvents (in water solvent) are defined as kosmotropic (order-making) if they contribute to the stability and structure of water-water interactions. Kosmotropes cause water molecules to favorably interact, which also (in effect) stabilizes intramolecular interactions in macromolecules such as proteins. Chaotropic agents (disorder-makers) have the opposite effect, disrupting water structure, increasing the solubility of nonpolar solvent particles, and destabilizing solute aggregates.
Ionic kosmotropes tend to be small or have high charge density. Some ionic kosmotropes are CO2−
4, magnesium(2+), lithium(1+), zinc (2+) and aluminium (+3). Large ions or ions with low charge density (such as bromide, iodide, potassium(1+), caesium(1+)) instead act as chaotropes. Kosmotropic anions are more polarizable and hydrate more strongly than kosmotropic cations of the same charge density.
A scale can be established if one refers to the Hofmeister series or looks up the free energy of hydrogen bonding () of the salts, which quantifies the extent of hydrogen bonding of an ion in water. For example, the kosmotropes CO2−
3 and OH−
have between 0.1 and 0.4 J/mol, whereas the chaotrope SCN−
has a between −1.1 to −0.9.
Ammonium sulfate is the traditional kosmotropic salt for the salting out of protein from an aqueous solution. Kosmotropes are used to prevent protein aggregation in pharmaceutical preparation and at various stage of protein extraction and purification. They act by stabilizing native intramolecular protein interactions, thus out-competing the intermolecular interactions that lead to aggregation.
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