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To elucidate the kinetic importance of structural intermediates in single-domain proteins, we measured the effect of solution conditions and amino-acid changes at a central core residue of ubiquitin (Val 26) on the kinetics of folding and unfolding. Kinetic analysis in terms of a sequential three-state mechanism provides insight into the contribution of specific interactions within the ubiquitin core to the structural stability of the native and intermediate states. The observations that disruptive mutations and/or addition of denaturants result in an apparent two-state folding process with slower rates is explained by the destabilization of a partially folded intermediate, which is in rapid equilibrium with unfolded states. The model predicts that under sufficiently stabilizing conditions kinetic intermediates may become populated even for proteins showing apparent two-state kinetics.

Type

Journal article

Journal

Nat Struct Biol

Publication Date

02/1996

Volume

3

Pages

193 - 205

Keywords

Humans, Kinetics, Models, Chemical, Models, Molecular, Mutation, Protein Denaturation, Protein Folding, Spectrometry, Fluorescence, Ubiquitins, Valine