Computational Chemical and Structural Biology
Six of the ten most frequent protein topologies have symmetry on the fold level. We postulate that the evolutionary origin of these symmetric superfolds lies in naturally occurring homo-oligomeric protein complexes that undergo gene duplication and fusion. To test this hypothesis the Rosetta protein design package was used to computationally design a two-fold symmetric variant of imidazole glycerol phosphate synthase (HisF). The new protein, termed FLR, adopts the symmetric βα TIM-barrel superfold. The experimental structure of FLR exhibits two-fold symmetry on the sequence and structural level. When cut in half, FLR dimerizes readily to adopt the same fold. FLR thereby mimics a hypothetical, ancestral symmetric gene-fused monomer of HisF. Design of symmetric proteins requires reduced computational resources and thereby presents an attractive strategy for the construction of larger proteins.