HIGH-RESOLUTION PROTEIN DESIGN WITH BACKBONE FREEDOM

Recent advances in computational techniques have allowed the design of precise side-chain packing in proteins with predetermined, naturally occurring backbone structures. Because these methods do not model prot ein main-chain flexibility, they lack the breadth to explore novel bac kbone conformations. Here the de novo design of a family of or-helical bundle proteins with a right-handed superhelical twist is described. In the design, the overall protein fold was specified by hydrophobic-p olar residue patterning, whereas the bundle oligomerization state, det ailed main-chain conformation, and interior side-chain rotamers were e ngineered by computational enumerations of packing in alternate backbo ne structures. Main-chain flexibility was incorporated through an alge braic parameterization of the backbone. The designed peptides form ct- helical dimers, trimers, and tetramers in accord with the design goals . The crystal structure of the tetramer matches the designed structure in atomic detail.