Complete change of the protein folding transition state upon circular permutation.
Reversing the loop lengths of the small protein S6 by circular permutation has a dramatic effect on the transition state structure: it changes from globally diffuse to locally condensed. The phenomenon arises from a biased dispersion of the contact energies. Stability data derived from point mutations throughout the S6 structure show that interactions between residues that are far apart in sequence are stronger than those that are close. This entropy compensation drives all parts of the protein to fold simultaneously and produces the diffuse transition-state structure typical for two-state proteins. In the circular permutant, where strong contacts and short sequence separations are engineered to concur, the transition state becomes atypically condensed and polarized. Taken together with earlier findings that S6 may also fold by a 'collapsed' trajectory with an intermediate, the results suggest that this protein may fold by a multiplicity of mechanisms. The observations indicate that the diffuse transition state of S6 is not required for folding but could be an evolutionary development to optimize cooperativity.
D007700:Kinetics; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D038601:Ribosomal Protein S6 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013816:Thermodynamics
D010456:Peptides, Cyclic; D038601:Ribosomal Protein S6