title: Different circular permutations produced different folding nuclei in proteins: a computational study.
abstract: There have been many studies about the effect of circular permutation on the transition state/folding nucleus of proteins, with sometimes conflicting conclusions from different proteins and permutations. To clarify this important issue, we have studied two circular permutations of a lattice protein model with side-chains. Both permuted sequences have essentially the same native state as the original (wild-type) sequence. Circular permutant 1 cuts at the folding nucleus of the wild-type sequence. As a result, the permutant has a drastically different nucleus and folds more slowly than wild-type. In contrast, circular permutant 2 involves an incision at a site unstructured in the wild-type transition state, and the wild-type nucleus is largely retained in the permutant. In addition, permutant 2 displays both two-state and multi-state folding, with a native-like intermediate state occasionally populated. Neither the wild-type nor permutant 1 has a similar intermediate, and both fold in an apparently two-state manner. Surprisingly, permutant 2 folds at a rate identical with that of the wild-type. The intermediate in permutant 2 is stabilised by native and non-native interactions, and cannot be classified simply as on or off-pathway. So we advise caution in attributing experimental data to on or off-pathway intermediates. Finally, our work illuminates the results on alpha-spectrin SH3, chymotrypsin inhibitor 2 and beta-lactoglobulin, and supports a key assumption in the experimental efforts to locate potential nucleation sites of real proteins via circular permutations.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA, 02138, USA.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: E I
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D003198:Computer Simulation; D007700:Kinetics; D007782:Lactoglobulins / Q000737:chemistry; D009010:Monte Carlo Method; D010455:Peptides / Q000737:chemistry; D010940:Plant Proteins; D015202:Protein Engineering; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013049:Spectrin / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics
chemical_list: D007782:Lactoglobulins; D010455:Peptides; D010940:Plant Proteins; D011506:Proteins; C093336:chymotrypsin inhibitor 2; D013049:Spectrin