Protein , conformational states compact denatured state

The folding of proteins into their characteristic three-dimensional shape is governed primarily by noncovalent interactions. Hydrogen bonding governs the formation of a helices and [) sheets and bends, while hydrophobic effects tend to drive the association of nonpolar side chains. Hydrophobicity also helps to stabilize the overall compact native structure of a protein over its extended conformation in the denatured state, because of the release of water from the chain s hydration sheath as the protein... 

A puzzling problem was posed by Levinthal many years ago.329 We usually assume that the peptide chain folds into one of the most stable conformations possible. However, proteins fold very rapidly. Even today, no computer would be able, in our lifetime, to find by systematic examination the thermodynamically most stable conformation.328 It would likewise be impossible for a folding protein to "try out" more than a tiny fraction of all possible conformations. Yet folded and unfolded proteins often appear to be in a thermodynamic equilibrium Experimental results indicate that denatured proteins are frequently in equilibrium with a compact denatured state or "molten globule" in which hydrophobic groups have become clustered and some secondary structures exists.330-336 From this state the polypeptide may rearrange more slowly through other folding intermediates to the final "native conformation."3363 3361 ... 

Fig. 7. Simple schematic diagram representing three conformational states of proteins The expanded denatured state whose structure is determined by steric interactions the compact denatured state, with structure determined by hydrophobic buril and the native state, with structure determined by dispersion forces, hydrogen bonds, and electrostatics.

The specific enthalpy and entropy of the conformation transition of proteins from the native to denatured state has an upper limit that is reached above 140°C and seems to be universal for all compact globular proteins (Figs. 4 and S). By enthalpy and entropy of conformational tran-... 

However, many experimental studies indicate that denatured globular proteins do not show necessarily complete exposure to solvent but can be more or less compact conformations or even can retain significant amounts of ordered structures besides, there is experimental evidence that for a given protein different denatured states can exist, depending on the denaturation agent and conditions. 

When the urea and thiol are removed by dialysis (see p. 78), secondary and tertiary structures develop again spontaneously. The cysteine residues thus return to a suf ciently close spatial vicinity that disulfide bonds can once again form under the oxidative effect of atmospheric oxygen. The active center also reestablishes itself In comparison with the denatured protein, the native form is astonishingly compact, at 4.5 2.5 nm. In this state, the apolar side chains (yellow) predominate in the interior of the protein, while the polar residues are mainly found on the surface. This distribution is due to the hydrophobic effect (see p. 28), and it makes a vital contribution to the stability of the native conformation (B). 

Changing solvent conditions can have a tremendous impact on the folding reaction. The well-known denaturing effect of some solvents on proteins was extended to foldamers by Moore, who showed that chloroform leads to a random coil conformation in mPE oligomers while acetonitrile promotes a compact, folded, helical state. 

The 3D structure of a protein molecule is the net result of the covalent structure (primary structure), noncovalent interactions, and conformational entropy. Table 13.3, summarizing the various interactions, compares the compact native (N) state with the completely unfolded denatured (D) state. Which state is promoted depends on the sign of which contains an enthalpic and an entropic term ... 

---