Beta/alpha barrel (or TIM barrel) structures display radial symmetry of arrangement of supersecondary structural motifs known as beta/alpha units. In this paper, we shuffle or scramble the locations of such motifs in yeast triosephosphate isomerase (TIM) through protein engineering and show that, in certain engineered variants, profoundly scrambled chains still retain the ability to fold into TIM barrels. The insight gained is that there is plasticity of formation of hydrophobic contacts in the core beta barrel within the larger beta/alpha barrel, as well as plasticity in the formation of hydrogen bonds amongst beta strands in the core beta barrel. This opens up the way to use beta/alpha units as modules which can be moved around within, or between, beta/alpha barrel-based protein structures.

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