Globular Proteins and Folding

There are many globular proteins in a living cell, and they play a key role. We have already discussed this in Chapter 5. However, the theory of such systems is extremely hard a protein globule is perhaps one of the most complex objects in modern physics. What is striking and unusual is that proteins have a strictly defined spatial tertiary structure (see Sections 5.6.4 and 5.7). In a protein globule, not only averaged density, but the entire spatial structure of the whole chain is fixed. 

By contrast, how is the fixed tertiary structure created Perhaps there is some other mysterious machine , of which we know nothing at all, but 

As a matter of fact, as usual in biology, every rule seems to have at least some exceptions. Some complex proteins fold with the help of special molecules, called chaperones. Nevertheless, a firmly established fact is that many proteins do not need any assistance and are able to do this amazing job easily and reliably on their own. Moreover, from the physics point of view, does it really make a great difference whether it is just one protein molecule that organizes itself, or a pair of molecules, such as a protein and a chaperone  

in contrast to the primary structure which can only be produced in the living factory , the tertiary structure is capable of organizing itself. In this sense, the formation of primary structure is in the subject of biology. 

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The peptide chain in globular proteins is folded into fairly compact conformations. Water-soluble enzymes are typical globular proteins which have most of the hydrophobic amino acid residues located in the interior and the hydrophilic residues located mainly at the surface in contact with solvent water. The average radii are 20-40 A (Boyer, 1970). It is clear that there are common morphological features between surfactant micelles and enzyme molecules. This fact has prompted many chemists to use micelles as enzyme models. However, it must be emphasized that micelles exist in dynamic equilibria with monomeric surfactant and their hydrophobic core is quite fluid, whereas enzyme molecules have precisely fixed three-dimensional structures. 

Figure 11.5 Globular proteins. The folding of a polypeptide chain in a globular form is stabilized by hydrophobic interactions and some covalent bonding, particularly the disulphide bond between cysteine residues. The polypeptide chain shows some sections which are regular and helical in nature and other sections, particularly at bends and folds, where the conformation of the chain is distorted.

The nature of the amino acid residues is of prime importance in the development and maintenance of protein structure. Polypeptide chains composed of simple aliphatic amino acids tend to form helices more readily than do those involving many different amino acids. Sections of a polypeptide chain which are mainly non-polar and hydrophobic tend to be buried in the interior of the molecule away from the interface with water, whereas the polar amino acid residues usually lie on the exterior of a globular protein. The folded polypeptide chain is further stabilized by the presence of disulphide bonds, which are produced by the oxidation of two cysteine residues. Such covalent bonds are extremely important in maintaining protein structure, both internally in the globular proteins and externally in the bonding between adjacent chains in the fibrous proteins. 

Both the denaturation process in proteins and the melting transition (also referred to as the helix-to-coil transition) in nucleic acids have been modeled as a two-state transition, often referred to as the all-or-none or cooperative model. That is, the protein exists either in a completely folded or completely unfolded state, and the nucleic acid exists either as a fully ordered duplex or a fully dissociated monoplex. In both systems, the conformational flexibility, particularly in the high-temperature form, is great, so that numerous microstates associated with different conformers of the biopolymer are expected. However, the distinctions between the microstates are ignored and only the macrostates described earlier are considered. For small globular proteins and for some nucleic acid dissociation processes,11 the equilibrium between the two states can be represented as... 

In globular proteins, the folding of the polypeptide chain is such that the amino acids with nonpolar side chains are assembled in the interior to form a hydro-phobic core, whereas the amino acids with polar and charged side chains tend to be at the surface to interact with the (aqueous) solvent. This oil-drop-like distribution of hydrophilic and hydrophobic amino acids is of importance for the functionality and stability of a protein because pK values of acidic and basic side chains can be shifted in nonpolar environment by several units, and internal hydrogen bonds are strengthened because the donors and acceptors do not have to compete with water molecules [133, 134J. 

Table V shows that the vast majority of the titratable groups of the smaller protein molecules have pK nt values which are quite close to the values predicted from the pK s of model compounds. This feature of protein titration curves has been well known for a long time, and is accepted as normal. It is however really an astonishing result, for it implies that most of the titratable groups of the smaller protein molecules are in as intimate contact with the solvent as similar groups on smaller molecules, and that they are able to accept or release hydrogen ions in this location without requiring any modification of the protein conformation in the vicinity of the titratable group. Since most of the proteins examined have been globular proteins, tightly folded so as to exclude solvent from most of the interior portions, the titratable groups must be nearly always at the surface.

Degree of Folding in Globular Proteins and the Rotatory Dispersion... 

Molecules of globular proteins are folded into compact units that often approach spheroidal shapes. The folding takes place in such a way that the hydro-phobic parts are turned inward, toward each other, and away from water hydrophilic parts—charged groups, for example—tend to stud the surface where they are near water. Hydrogen bonding is chiefly intramolecular. Areas of contact between molecules are small, and intermolecular forces are comparatively weak. 

Furthermore, amino add pair-specific interactions and higher-order tertiary and quaternary interactions may be responsible for the selection of the native fold or the destabilization of an alternative structure [164]. Such interactions may be electrostatic in origin or arise from the complex interplay of potentials of mean force. Thus, there are a variety of interactions present in a globular protein, and the native structure is the result of a balance of such terms. 

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