Developing a stable therapeutic protein formulation requires an intimate knowledge of the protein and its physical and chemical properties. In this article, Bernardo Perez-Ramirez and Robert Simler discuss the thermodynamic consequences that low temperature can have on the aggregation tendencies of a protein.

Proteins are dynamic entities, constantly adopting different partially-folded states as a function of temperature and other solution variables. These variables dictate the standard free energy between the native, unfolded and partially folded aggregation prone states leading to oligomerisation. As a result, not all oligomerisation events in proteins are similar. Altering these variables, such as temperature, pH, salt and ligands, could induce a protein to aggregate as a consequence of unnatural folding to balance the thermodynamically unfavourable interactions between solvent and exposed hydrophobic residues in proteins. In the same way, these variables may induce a protein to self-associate, in mostly the native state, to counteract the unfavourable interactions with the solvent. Thus, cold instability without inducing cold denaturation could destabilise the native state of a protein, making it more prone to aggregation events.

View post:

Thermodynamic probes of instability: application to therapeutic proteins - European Pharmaceutical Review