Abstract
Protein folding occurs because the native interactions collectively outweigh non-native interactions, resulting in funnel-shaped energy landscapes. The funnel-shaped landscapes of natural proteins are rugged due to evolution for function or neutral drift. We describe an approach to designing ideal protein structures stabilized by consistent local and non-local interactions. The approach is based on rules relating local structures to tertiary motifs, which make possible the design of strongly funneled energy landscapes. Guided by these rules, we succeeded in designing five ideal alpha-beta protein structures with different topologies completely from scratch. These results illuminate how the folding funnels of natural proteins arise.
