Researchers in the field of rational protein design face a significant challenge, which arises from the two defining and inter-related features of typical globular protein structures, namely topological complexity and cooperativity. In striking contrast to globular proteins, tandem repeat proteins, such as ankyrin, tetratricopeptide and leucine-rich repeats, have regular, modular, linearly arrayed structures which makes it especially straightforward to dissect and redesign their properties. Here we review what we have learnt about the biophysics of natural repeat proteins and recent progress in applying that knowledge to engineer the thermodynamics, folding pathways and molecular recognition properties of tandem repeat proteins, and we discuss the wealth of possibilities presented for the extension of this modular construction process to build new molecules for use in medicine and biotechnology. © 2013 Elsevier Ltd.
