Design of structurally distinct proteins using strategies inspired by evolution

Building new proteins from the old Proteins are the workhorses of biology. Designing new, stable proteins with functions desirable in biotechnology or biomedicine remains challenging. Jacobs et al. developed a computational method called SEWING that designs proteins using pieces of existing structures (see the Perspective by Netzer and Fleishman). The new proteins can contain structural features such as pockets or grooves that are required for function. The solved structures of two designed proteins agreed well with the design models. The method allows rapid design of a diverse set of structures that will facilitate functional design. Science, this issue p. 687; see also p. 657 A design strategy builds new protein structures by recombining pieces of existing protein domains. Natural recombination combines pieces of preexisting proteins to create new tertiary structures and functions. We describe a computational protocol, called SEWING, which is inspired by this process and builds new proteins from connected or disconnected pieces of existing structures. Helical proteins designed with SEWING contain structural features absent from other de novo designed proteins and, in some cases, remain folded at more than 100°C. High-resolution structures of the designed proteins CA01 and DA05R1 were solved by x-ray crystallography (2.2 angstrom resolution) and nuclear magnetic resonance, respectively, and there was excellent agreement with the design models. This method provides a new strategy to rapidly create large numbers of diverse and designable protein scaffolds.