Take home lessons from studies of related proteins

The ‘Fold Approach’ involves a detailed analysis of the folding of several topologically, structurally and/or evolutionarily related proteins. Such studies can reveal determinants of the folding mechanism beyond the gross topology, and can dissect the residues required for folding from those required for stability or function. While this approach has not yet matured to the point where we can predict the native conformation of any polypeptide chain in silico, it has been able to highlight, amongst others, the specific residues that are responsible for nucleation, pathway malleability, kinetic intermediates, chain knotting, internal friction and Paracelsus switches. Some of the most interesting discoveries have resulted from the attempt to explain differences between homologues.