Structural biology: A toolbox for protein design

Some of the principles underlying how amino-acid sequences determine the three-dimensional structures of proteins have been defined. This has enabled a successful approach to designing protein folds from scratch. See Article p.222 When natural proteins folds to produce their unique biologically adapted structure, they do so despite the many energetically unfavorable non-ideal features — such as kinked helices, strained loops and buried polar groups — that arise in proteins as a result of evolutionary selection for biological function or neutral drift. In this study, the authors describe a new approach to designing ideal protein structures stabilized by completely consistent local and non-local interactions. They generate a set of simple 'rules' that relate secondary-structure patterns to protein tertiary motifs and use these rules to design sequences that fold into more complex protein structures. The design principles and methodology described here should allow the design of a wide range of robust and stable protein building blocks for the next generation of engineered functional proteins.