Protein Folding An Overview

Prefolding State: The Molten Globule. In order for a protein to achieve a three-dimensional native state, it must undergo a large number of possible conformations rapidly, prior to achieving its final product. A problem for biochemists is understanding how a protein achieves its native state (N) or becomes folded. Anfinsen (14) discovered that a protein's amino acid sequence fully determines its three-dimensional structure and, thus, its biological function. Work from the late 1970s and early 1980s gave rise to the concept that the protein native (N) and unfolded states (U) were an all-or-none scenario (U <-> N) (15,16). Yet, although this theory was generally accepted, strong experimental evidence of proteins treated with high guanidine hydrochloride (GdnCl) concentrations showed large differences in hydrodynamic and optical parameters when compared to little changes in the presence of high temperatures and/ or low pH (plus addition of salts) (17). Evidence mounted for the existence of an intermediate equilibrium between the native and unfolded states. It was shown that temperature-denatured proteins are far from being completely unfolded and can undergo another cooperative transition when GdnCl or urea is added (18,19). Circular dichroism (CD) studies showed the existence of one or more equilibrium states that differed from the native state by the absence of the rigid aromatic side chains; at the same time, they differed from the unfolded states by the presence of secondary structure (18). The conclusion was made that these intermediates were unfolded, noncompact molecules with local secondary structure (20). These studies showed a physical state that existed between native and unfolded and was given the term molten globule (Fig. 1) (22).

Molten globule (MG), as a term, has been applied to all compact denatured states that have substantial secondary structure, but little or no tertiary structure. This can cover a wide range of ordered and disordered, partially folded proteins with and without disulfide bonds (23).

The molten globule conformation is frequently adopted rapidly where an unfolded protein is placed under refolding conditions before the appearance of the fully folded protein. Because of the prefolded state, occurrence of the molten globule (24) was thought to be an indicator of a kinetic intermediate and assigned the kinetic role of

This equation would imply that the molten globule is required for the formation of the native state. From this equation, the initial rate of forming N should be zero upon

Table 2. Linkages and Interactions Involved in Stabilizing Protein Conformation
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