Engineering aggregation-resistant proteins by directed evolution

A method was recently described for selecting aggregation-resistant antibody domains. A repertoire of domains displayed on filamentous bacteriophage were heated/cooled and selected for binding to the affinity ligand protein A specific for the folded domains. Here we describe a generalization of the method based on the selection for retained phage infectivity and for the binding of an appended sequence tag, and applicable to any protein displayable in multivalent form on phage.