Thermodynamics of transient conformations in the folding pathway of barnase: reorganization of the folding intermediate at low pH

Biochemistry
M Oliveberg, A R Fersht

Abstract

New classes of small proteins have recently been found that refold rapidly with two-state kinetics from a substantially unfolded conformation ("U") and without the accumulation of a folding intermediate. Barnase, on the other hand, is representative of a class of proteins that display multistate kinetics and refold from a partly structured conformation, a folding intermediate (I). The accumulation of I on the folding pathway of barnase is highly dependent on the experimental conditions: a transition from multistate to two-state folding behavior can be induced simply by changing the reaction conditions away from physiological, i.e., elevated temperatures, high concentration of denaturant, or low pH. We argue that the change in folding behavior results from the denatured state changing under different conditions. The denatured state seems compact and partly structured at conditions that favor folding but is disorganized at denaturing conditions. At physiological pH and temperature, the denatured state (Dphys) is the folding intermediate because it is the most stable of the denatured conformation, i.e., Dphys is identical to I. At high temperature or [urea], however, Dphys becomes destabilized relative to less structured denatured...Continue Reading

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Citations

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