Combinatorial Approaches to Constructing Protein Nanostructures

A major bottleneck in the use of proteins for the construction of complex nanostructures is the design of protein interfaces that will bind to one another with highaffinity and high specificity. The interaction of subunits with one another may be mediated by non-covalent, highaffinity protein-protein contacts, as is the case in many naturally occurring multi-subunit complexes. However, there are currently no well developed strategies for the design of complementary binding surfaces such as those required for the engineering of multi-subunit nanostructures. In the absence of a design paradigm, a promising alternative is the selection of tight binders from large, combinatorial libraries. The design specifications for these libraries include stability and physical robustness of the scaffold molecule; diversity of the displayed peptides; and ease of synthesis/expression.