Materials for Biomedical Engineering. Mohamed N. Rahaman

molecules composed of more than 10–20 residues are often called polypeptides. Consequently, a protein molecule is often called a polypeptide also.

      Proteins are large molecules, composed of ~50–2000 amino acid residues, but the peptide illustrated in Figure 2.18b, composed of five residues, shows the key features of the primary bonds in the chain backbone and examples of side groups attached to the chain backbone. The sequence of the amino acid residues in the chain backbone is called the primary structure of the protein. This primary structure dictates the higher‐order structure of proteins.

      2.6.2 Secondary Structure

      The term secondary structure describes the geometry of the long‐chain backbone of the individual protein macromolecule. This geometry can consist of randomly coiled chain along with regions composed of a regular repeating pattern. It is strongly influenced by two key factors

       The stereochemistry of the amide bond

       Hydrogen bonding between the oxygen atom of the carbonyl (C=O) group and the hydrogen atom of the amino (N–H) group in the chain backbone.

      Stereochemistry of the Amide Bond

A key feature of the amide bond is that the carbonyl (C=O) double bond resonates between the C–O and C–N positions, which gives the C–N bond partial double bond character (Figure 2.19a). The N atom has trigonal planar geometry, in a manner similar to carbon atoms in the ethylene molecule due to sp² hybridized electron orbitals (Section 2.4.2). Because rotation about a double bond is restricted, the amide bond has a planar geometry (Figure 2.19b). This has important consequences for the secondary and tertiary structure of the protein molecule.

Figure 2.19 Schematic illustration of the stereochemistry of the amide bond. (a) Resonance of the carbonyl (C=O) double bond, resulting in partial double bond character of the amine (N–H) bond. (b) Planar geometry of amide bond.

      Hydrogen Bonding

      Due to electronegativity differences between the atoms (Section 2.4), the carbonyl C=O and amino N–H bonds are polarized. Thus, the O and H atoms in these bonds have a partial negative ( δ ⁻) and positive charge ( δ ⁺), respectively. As the O atom also has lone pair electrons, this leads to hydrogen bonding between the O and H atoms of different amide groups that can occur within a chain (intrachain bonding) and between neighboring chains (interchain bonding). Hydrogen bonding is an important feature of both the secondary and higher order structures of proteins but the way it occurs within the chain controls the secondary structure.

      While the overall conformation of a protein is complex and unique, a feature of the chains themselves is that they often contain regions with two regular repeating patterns called the α‐helix and the β‐sheet. These two structures result from hydrogen bonding between the O atoms of the C=O group and the H atoms of the N–H group of the amide bond in the chain backbone, without involving the side chains.

An α‐helix is generated when a single protein chain twists around itself in the form of a helical geometry (Figure 2.20). Hydrogen bonds between every fourth peptide bond stabilizes the structure, giving a regular helix with a complete turn every 3.6 amino acid residues. To reduce steric hindrance to this type of intrachain bonding, the side groups attached to the chain backbone point outward from the chains. Other helices occur but they are less common.

Figure 2.20 Illustration of (a) α‐helix structure generated by intrachain hydrogen bonding in polypeptides, and (b) geometrical parameters of α‐helix. The side groups point outward from the chain.

The β‐sheet forms as a result of layering of the protein chain, one part on top of the other. This structure is stabilized by hydrogen bonds between neighboring parts of the chain (Figure 2.21). These β‐sheets can form in two ways, either from neighboring protein chains that run in the same orientation (called parallel chains) or from an individual protein chain that runs back and forth (antiparallel chains). This arrangement of the chain backbone along with hydrogen bonding results in both types of β‐sheet having a rather rigid structure. The side groups are at right angles to the sheets, minimizing steric hindrance between the layers. Regions of β‐sheets are common in many proteins because of their efficient packing.

Figure 2.21 Illustration of β‐sheet structure generated by layering of polypeptide chains and hydrogen bonding between the chains: (a) parallel β‐sheet, (b) antiparallel β‐sheet, and (c) β‐turn in antiparallel β‐sheet.

      In forming an antiparallel β‐sheet, the chain backbone of the protein changes its direction, turning back and forth upon itself, making what is described as a β‐turn. This is an important feature of protein folding, which gives a more compact shape. A hydrogen bond between the first and third peptide residues of the β‐turn and the amino acid proline are frequently found at bends in the chain backbone (Figure 2.21c). Of the 20 α‐amino acids (Figure 2.17), proline is the only one in which the side chain is connected to the chain backbone twice, forming a five‐membered nitrogen‐containing ring. Because ring structures typically have limited flexibility, proline is unable to occupy many of the main‐chain conformations easily adopted by other amino acids. Proline is also nonpolar and, thus, cannot take part in hydrogen bonding. Together, these factors make proline a useful residue for occupying tight turns in a protein structure such as the β‐turn.

      2.6.3 Tertiary Structure

The tertiary structure of a protein refers to the overall three‐dimensional shape (conformation) of its polypeptide chain. Many proteins do not have the regular structure of the α‐helix or β‐sheet but, instead, rely for their properties on their tertiary structure. A polypeptide chain can fold in a complex manner to give a variety of three‐dimensional shapes, but two broad classes of structures, referred to as globular and fibrous, are often distinguished. In globular proteins, the polypeptide chain is more compactly folded like a ball of string with an irregular surface. In comparison, the polypeptide chain in fibrous proteins have a more elongated or filamentous three‐dimensional structure (Figure 2.22).