Proteins are made of amino acids that interact with water through their amino acid residues on the surface. The hydrophilic amino acids include argenine, aspartic acid glutamic acid and lysine. Depending on the pH of the solvent the charges of the amino acid's side chains change. At pH 7 arginine and lysine carry a positve charge, aspartic acid and glutamic acid carry a negative charge.
Lysine and arginine begin to lose their positive charge as the pH increases. They are mainly neutral at pHs greater than 12. If the pH decreases on the other hand, aspartic acid and glutamic acid begin to lose their negative charges and are mainly neutral at pHs less than 4.
The solubility of a protein depends on the net charge on the surface of a protein. The net charge depends on the pH of the solvent and the number Hertford Aggregates and identities of the amino acids that make up the protein .
The isoelectric point of a protein occurs at a specific pH when the positive and negative charges balance each other out and the net charge is zero. At this isoelectric point a protein is least soluble. For most proteins this occurs in the pH range of 5.5 to 8. A protein gets more soluble if there is a net charge at the protein surface, since it prefers to interact with water, rather than with other protein molecules. Without a charge at the surface proteins are likely precipitate and aggregate.
There are many ways to transform protein aggregate into the proper solubilized state. Depending on the state of the aggregated protein material and the sought after utility of the solubilized protein material the solubilization conditions will likely require screening different solubilization reagents (additives) and solubilization techniques. Appropriate analytical tools are required to assess the progress of such an optimization trial.
Alternatively there are protein solubility optimization kits available now to help determine optimal conditions for different proteins.
A helpful online tool to predict Protein Solubility starting from amino acid sequence has been developed by the Univ. Oklahoma, School of Chemical Engineering and Materials Science.: