Colloidal protein-protein interactions (PPI) in solution have a dramatic effect on protein stability and protein self-assembly. These interactions are important for applications ranging from protein phase behavior to aggregation of biopharmaceuticals. However, the nature of these interactions is poorly understood since it is affected by several factors such as temperature and protein sequence. Mutation of one amino acid in a protein can dramatically affect the aggregation propensity. Here we analyze, via coarse-grained molecular modeling, the role of these interactions on the stability and aggregation propensity of human ?D-Crystallin, a natively monomeric two-domain protein. By considering proteins as folded rigid bodies that interact through van der Waals, hydrophobic, and screened Coulomb forces between individual amino acids, the thermodynamic stability of the wild type protein, as well as a series of surface charge mutants, is evaluated. RosettaDesign is also used to minimize disruption of conformational stability as part of the design strategy.  Interestingly, no simple relation between PPI and aggregation propensity was found, as, for instance, changes on the protein net charge do not always yield the same effect on inherent aggregation propensity �quantitatively or qualitatively. The results are compared against experimental data for some of these mutants, suggesting the methods may be applicable more generally.

Applying coarse-grained molecular models for rational design of colloidal protein-protein interactions to mitigate aggregation

243rd National Meeting (2012)

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