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A Variety of Forces Maintain the 3-D Structure of Proteins 165

FIGURE 7.12 Inverse Conformation of a Membrane Protein

The hydrophilic regions of membrane proteins interact with the aqueous cell interior and exterior. Their hydrophobic regions face the hydrophobic phospholipds of the membrane.

Hydrophilic

Hydrophilic

FIGURE 7.12 Inverse Conformation of a Membrane Protein

The hydrophilic regions of membrane proteins interact with the aqueous cell interior and exterior. Their hydrophobic regions face the hydrophobic phospholipds of the membrane.

Hydrophilic

Hydrophilic

Hydrophobic amino acids tend to cluster together inside proteins so promoting 3D folding.

arrangement is known as the oil drop model of protein structure. The terms hydropho-bic interaction, hydrophobic bonding or apolar bonding all refer to the tendency of non-polar groups to cluster together and avoid contact with water.

The formation of hydrophobic bonds is driven mostly by effects on water structure, not by any inherent attraction of hydrophobic groups for each other. Strictly, the term hydrophobic (which means "fearing/disliking water") is misleading as it is the water which dislikes the dissolved non-polar groups. Exposed hydrocarbon residues exert an organizing effect on surrounding water molecules. This decreases the entropy of the water and is thermodynamically unfavorable. Removal of hydrocarbon residues allows the water to return to its less organized H-bonding structure, which results in a large increase in entropy (approximately 0.7 Kcal per methylene group removed).Thus removing a leucine side chain from contact with water releases 3.5 Kcal/mole. Because the hydrophobic interaction depends on entropy, the strength of hydrophobic bonding increases with temperature, unlike most other forms of bonding which become less stable at higher temperatures.

Proteins that are inserted deeply into membranes show a conformation that is the inverse of the standard oil drop. They are hydrophobic on the surfaces where they contact the membrane lipid. Their hydrophilic residues are mostly clustered internally, but some are found at the surface in those regions where the protein emerges from the membrane (Fig. 7.12).

Hydrophilic amino acids often end up on the surface of folded proteins where they make contact with water.

A Variety of Forces Maintain the 3-D Structure of Proteins

In addition to the major influence of hydrophobic interactions in the core of the protein and the hydrogen bonding of hydrophilic side chains to water, a variety of other effects are important (Fig. 7.13). These include hydrogen bonds, ionic bonds, van der Waals forces, and disulfide bonds.

Hydrogen bonds may form between the R-groups of two nearby amino acids. Those amino acids with hydroxyl, amino or amide groups in their side chains can take part in such hydrogen bonding. Similarly, ionic bonds (—NH3+ -OOC—) may form between the R-groups of basic and acidic amino acid residues (Fig. 7.13). Relatively few of the possible ionic interactions occur in practice. This is because most polar groups are on the surface of the protein and form hydrogen bonds to water.

Van der Waals forces hold molecules or portions of molecules together if they fit well enough to approach very closely. Van der Waals forces are weak and decrease very rapidly with distance. Consequently, they are only significant for fairly large regions that are complementary in shape. Disulfide bonds between cysteines are also sometimes important in maintaining 3-D structure (see below).

oil drop model Model of protein structure in which the hydrophobic groups cluster together on the inside away from the water

Hydrophobic Ionic Disulfide Hydrogen Hydrophobic bond bond bond bond cluster

FIGURE 7.13 Some Forces that Maintain 3-D Structure of Proteins

Hydrophobic Ionic Disulfide Hydrogen Hydrophobic bond bond bond bond cluster

FIGURE 7.13 Some Forces that Maintain 3-D Structure of Proteins

Other forces that maintain the 3-D structure include: A) hydrophobic ring stacking, B) ionic bonds, C) disulfide bonds, D) hydrogen bonds and E) hydrophobic clustering.

Disulfide bonds between two cysteine residues can stabilize protein structures.

Cysteine Forms Disulfide Bonds

Under oxidizing conditions, the sulfhydryl groups of two cysteines can form a disulfide bond. The dimer consisting of two cysteines (pronounced "cystEEn") joined by a disulfide bond is known as cystine (pronounced "cystYne") (Fig. 7.14). Disulfide bonds between cysteine residues are important in maintaining 3-D structure in certain cases (see Fig. 7.13, above). Disulfide bonds may hold together two regions of the same polypeptide chain (intrachain disulfide bond for tertiary structure) or may be used to hold together two separate polypeptides (interchain disulfide bond for quaternary structure).

Since disulfides are easily reduced to sulfhydryl groups inside cells, they are of little use in stabilizing intracellular proteins. Disulfide bonds are mostly used to stabilize extracellular proteins that are exposed to more oxidizing conditions. The classic examples are the antibodies that circulate in the blood of vertebrates. Secreted enzymes, such as lysozyme, or hormones, such as insulin, also rely on disulfide bonds. Single-celled organisms make relatively few extracellular proteins compared to higher multi-cellular organisms and consequently employ disulfide bonding much less.

In long proteins folding may occur separately in different regions of the polypeptide chain.

Multiple Folding Domains in Larger Proteins

Long polypeptide chains may contain several regions that fold up more or less independently and are joined by linker regions with little 3-D structure. Such regions are known as domains and may be from 50-350 amino acids long (Fig. 7.15). Short proteins may have a single domain and extremely long proteins may occasionally have up to a dozen.

Note that proteins begin to fold before they are completely made. As soon as a sufficient length of polypeptide chain to form a 3-D structure has emerged from the ribosome, it folds. Hence domains fold up independently, one after the other. (Because disulfide bond A sulfur to sulfur bond formed between two sulfhydryl groups, in particular between those of cysteine, and which binds together two protein chains domain (of protein) A region of a polypeptide chain that folds up more or less independently to give a local 3D-structure lysozyme Enzyme that degrades peptidoglycan, the cell wall polymer of bacteria

Quaternary Structure of Proteins 167

FIGURE 7.14 Cysteine and Cystine

Two cysteines will join by a disufide bond to form cystine.

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