Protein aggregation in salt solutions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 21; pp. 6766 - 6770
• Main Authors: Kastelic, Miha, Kalyuzhnyi, Yurij V., Hribar-Lee, Barbara, Dill, Ken A., Vlachy, Vojko
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26-05-2015; National Acad Sciences
• Subjects: Accuracy; Biological Sciences; Crystallization; Experiments; gamma-Crystallins - chemistry; Models, Chemical; Muramidase - chemistry; Osmosis; Protein Aggregates; Proteins; Proteins - chemistry; Saline water; Salts; Solutions; Systems Biology; Thermodynamics; phase separation; Hofmeister series; protein aggregation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1507303112

Protein aggregation is broadly important in diseases and in formulations of biological drugs. Here, we develop a theoretical model for reversible protein–protein aggregation in salt solutions. We treat proteins as hard spheres having square-well-energy binding sites, using Wertheim’s thermodynamic perturbation theory. The necessary condition required for such modeling to be realistic is that proteins in solution during the experiment remain in their compact form. Within this limitation our model gives accurate liquid–liquid coexistence curves for lysozyme and [Formula] IIIa-crystallin solutions in respective buffers. It provides good fits to the cloud-point curves of lysozyme in buffer–salt mixtures as a function of the type and concentration of salt. It than predicts full coexistence curves, osmotic compressibilities, and second virial coefficients under such conditions. This treatment may also be relevant to protein crystallization.
Significance Protein aggregation is a problem in amyloid and other diseases, and it is a challenge when formulating solutions of biological drugs, such as monoclonal antibodies. The physical processes of aggregation, especially in salt solutions, are not well understood. We model a protein as having multiple binding sites to other proteins, leading to orientational variations, dependent on salt. With few parameters and with knowledge of the cloud-point temperatures as a function of added salt, the model gives good predictions for properties including the liquid–liquid coexistence curves, the second virial coefficients, and others for lysozyme and gamma-crystallin.