The vastness of unexplored protein fold universe remains a significant question. Through systematic de novo design of proteins with novel αβ-folds, we demonstrated that nature has only explored a tiny portion of the possible folds. Numerous possible protein folds are still untouched by nature. This review outlines this study and discusses the prospects for design of functional proteins with novel folds.
Keywords: novel fold; protein design; protein fold; protein sequence space; protein topology.
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