Designability of α-helical proteins

A typical protein structure is a compact packing of connected α-helices and/or β-strands. We have developed a method for generating the ensemble of compact structures a given set of helices and strands can form. The method is tested on structures composed of four α-helices connected by short turns. All such natural four-helix bundles that are connected by short turns seen in nature are reproduced to closer than 3.6 Å per residue within the ensemble. Because structures with no natural counterpart may be targets for ab initio structure design, the designability of each structure in the ensemble—defined as the number of sequences with that structure as their lowest-energy state—is evaluated using a hydrophobic energy. For the case of four α-helices, a small set of highly designable structures emerges, most of which have an analog among the known four-helix fold families; however, several packings and topologies with no analogs in protein database are identified.