The usage of protein folds in nature is known to be non-uniform: a few folds are used often, while most others are used relatively rarely. What makes one fold more successful than another? The designability explanation, which posits that successful folds have an exponentially larger number of compatible sequences, is critically reviewed, and compared with other structural and functional explanations. It is argued that designability is one component of fold fitness, but most likely not a dominant one.
Keywords: protein evolution, designability, protein folding, protein design, in vitro evolution
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