Researchers at the Institute for Protein Design have developed a novel computational approach for the custom design of hyper-stable alpha-helical bundles with fine-tuned geometries. The parametric design approach and experimental characterization of the resulting helical bundles is described in detail in a recent Science publication entitled High thermodynamic stability of parametrically designed helical bundles.

At the focus of the paper are coiled coils – a specific structural motif where two or more alpha helices twist around one another to form a supercoil. Coiled coil-based proteins play a number of important roles in biology and due to their simple and repetitive nature, have been the inspiration for a number of protein design efforts. Notably, Dr. Francis Crick proposed the concept of the coiled coil along with a set of mathematical methods for determining their structure .

To arrive at custom desiged protein folds that do not exist in nature, IPD researchers and their collaborators developed a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil-generating equations that also utilized the Rosetta protein design methodology. Three distinct helical bundle arrangements were designed and combinatorial design calculations identified the lowest energy sequences for each supercoil arrangement. Expression and purification of these structures in the laboratory and subsequent characterization showed that these designed proteins are extremely stable and their crystal structures show very strong agreement with the design models. This new approach enables the custom design of hyperstable proteins with fine-tuned geometries for a wide range of applications including next-generation nanostructures, therapeutics, and catalysts.