Figure 2.24 Illustration of chain folding of protein to form a globular three‐dimensional shape in an aqueous environment. Side groups with polar or ionizable molecules gather on the outside of the protein chain backbone whereas side groups with nonpolar molecules are buried on the inside of the chain. Some side groups are shown as examples.

      In nonaqueous environments, such as the lipid bilayer of the cell membrane, the arrangement of the polar and nonpolar groups is opposite to that in aqueous environments. The nonpolar groups predominantly gather on the outside of the protein chain where they can interact with the nonpolar (hydrophobic) side chains of membrane fatty acids whereas the polar groups arrange themselves anywhere they can contact water. For transmembrane proteins, for example, which project through both sides of the membrane, the polar groups are found at each point where the polypeptide chain emerges from the membrane.

      Fibrous Proteins

      Fibrous proteins are abundant in mammalian tissues, particularly in the extracellular matrix, a complex structural network of proteins and other substances surrounding and supporting cells. Extracellular matrix proteins are secreted by cells into their surroundings where they often assemble into sheets or fibers. The most abundant of these proteins is a family called collagen. A major component of skin and bone, collagen is the most abundant protein in mammals, comprising approximately 25% of the total dry protein mass.

Collagen is structurally distinct from other proteins in that the molecule consists of three polypeptide chains, called α‐chains, that wind around each other to form a long triple‐helix structure (Figure 2.25). Glycine, the smallest amino acid, occurs at every third position in the chain backbone. This small size and regular repeating pattern of glycine allows the three chains to wind around each other closely to generate a compact triple‐helix structure. Procollagen molecules secreted from cells are cleaved at their ends to form collagen molecules, each ~1.5 nm in diameter and ~300 nm in length. Side‐to‐side and end‐to‐end bonding between many of these collagen molecules lead to the formation of much larger fibrils that, in turn, can then assemble to form fibers (Chapter 10). This fibrous morphology is a significant factor in endowing tissues such as tendons and ligaments with their high tensile strength and elastic modulus, in a manner similar to aligned macromolecules that contribute to the high mechanical properties of synthetic fibers such as nylon and polyethylene.

Figure 2.25 (a) Illustration of single α‐chain composed of the amino acid sequence Gly‐X‐Y where Gly is the three letter symbol for glycine that occurs at every third position in the sequence, and X and Y are the one‐letter symbol of any amino acid. (b) Illustration of triple‐helix structure of collagen formed by winding of three α‐chains around each other.

As glycine (Gly) occurs at every third position, the primary structure of each chain has the sequence Gly‐X‐Y, where X and Y represent the one‐letter symbol of the other amino acid residues. X and Y can be any amino acid but, often, they consist of the amino acids proline (Pro) and hydroxyproline (three‐letter symbol Hyp). Typically, approximately one‐third of the amino acid residues in the chain consists of glycine and approximately one‐quarter consists of a combination proline and hydroxyproline, as exemplified by the amino acid content of human tendon (Table 2.5). Hydroxyproline and another modified amino acid, hydroxylysine (three‐letter symbol Hyl), which often occur in proteins, are formed by enzymatic reactions involving proline and lysine residues in the chain prior to triple‐helix formation within the cell (Figure 2.26).

Table 2.5 Measured amino acid content of human tendon.

Amino acid	Number of residues per 1000 residues
Glycine	334
Proline	122
Hydroxyproline	96
Acidic or polar (Asn; Glu; Asn)	124
Basic or polar (Lys; Arg; His)	91
Others	233

Figure 2.26 Schematic illustration of the structure of the modified amino acid residues hydroxyproline and hydroxylysine formed from proline and lysine residues by enzymatic reaction.

      Interchain hydrogen bonding between the carbonyl oxygen (C=O) and amine hydrogen (N–H) stabilizes the triple‐helix structure. Proline also plays a role in stabilizing the structure because it has a limited ability to change its conformation due to the ring structure of its side chain. As the triple‐helix already has a structure with the minimum energy due to the closely wound hydrogen‐bonded chains and the regular pattern of the amino acid residues, changes to its conformation to provide an entropic contribution to its free energy are not required. Thus, collagen molecules maintain a stable triple‐helix structure, unlike globular proteins that can undergo conformational changes.

      2.6.4 Quaternary Structure

Some globular proteins, often called oligomeric proteins, are composed of two or more different polypeptide chains. The quaternary structure of these proteins emphasizes the way in which the individual folded protein chains fit together to form an overall three‐dimensional structure (Figure 2.27). A well‐studied example is hemoglobin, the protein that carries oxygen in red blood cells. This protein has a nearly spherical shape, composed of two identical α‐globin subunits and two identical β‐globin subunits arranged symmetrically. The same noncovalent bonds that stabilize the tertiary structure stabilize the quaternary structure of proteins.

Figure 2.27 Illustrative example of quaternary structure of a protein composed of four polypeptide chains. In this example, there are two types of protein, labeled Protein 1 and Protein 2, each with two chains.

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