The CamSol Method of Rational Design of Protein Mutants with Enhanced Solubility

Protein solubility is often an essential requirement in biotechnological and biomedical applications. Great advances in understanding the principles that determine this specific property of proteins have been made during the past decade, in particular concerning the physicochemical characteristics of their constituent amino acids. By exploiting these advances, we present the CamSol method for the rational design of protein variants with enhanced solubility. The method works by performing a rapid computational screening of tens of thousand of mutations to identify those with the greatest impact on the solubility of the target protein while maintaining its native state and biological activity. The application to a single-domain antibody that targets the Alzheimer's Aβpeptide demonstrates that the method predicts with great accuracy solubility changes upon mutation, thus offering a cost-effective strategy to help the production of soluble proteins for academic and industrial purposes. [Display omitted] •Aggregation limits recombinant protein production and protein biologics development.•Antibodies are often poorly soluble at the concentrations needed for their delivery.•The CamSol method identifies protein mutants with enhanced solubility.•Tens of thousands of mutations can be screened in minutes on a laptop computer.