Protein Secondary Structure

The term secondary structure refers to the local conformation of some part of a polypeptide. The discussion of secondary structure most usefully focuses on common regular folding patterns of the polypeptide backbone. A few types of secondary structure are particularly stable and occur widely in proteins. The most prominent are the a helix and 3 conformations described below. Using fundamental chemical principles and a few experimental observations, Pauling and Corey predicted the existence of these secondary structures in 1951, several years before the first complete protein structure was elucidated.

The a Helix Is a Common Protein Secondary Structure

^ Protein Architecture—a Helix Pauling and Corey were aware of the importance of hydrogen bonds in orient ing polar chemical groups such as the C=O and N—H groups of the peptide bond. They also had the experimental results of William Astbury, who in the 1930s had conducted pioneering x-ray studies of proteins. Astbury demonstrated that the protein that makes up hair and porcupine quills (the fibrous protein a-keratin) has a regular structure that repeats every 5.15 to 5.2 A. (The angstrom, A, named after the physicist Anders J. Angstrom, is equal to 0.1 nm. Although not an SI unit, it is used universally by structural biologists to describe atomic distances.) With this information and their data on the peptide bond, and with the help of precisely constructed models, Pauling and Corey set out to determine the likely conformations of protein molecules.

The simplest arrangement the polypeptide chain could assume with its rigid peptide bonds (but other single bonds free to rotate) is a helical structure, which Pauling and Corey called the a helix (Fig. 4-4). In this structure the polypeptide backbone is tightly wound around an imaginary axis drawn longitudinally through the middle of the helix, and the R groups of the amino acid residues protrude outward from the helical backbone. The repeating unit is a single turn of the helix, which extends about 5.4 A along the long axis, slightly greater than the periodicity Astbury observed on x-ray analysis of hair keratin. The amino acid residues in an a helix have conformations with p = —45° to —50° and $ = —60°, and each helical turn includes 3.6 amino acid residues. The helical twist of the a helix found in all proteins is right-handed (Box 4-1). The a helix proved to be the predominant structure in a-keratins. More generally, about one-fourth of all amino acid residues in polypeptides are found in a helices, the exact fraction varying greatly from one protein to the next.

Why does the a helix form more readily than many other possible conformations? The answer is, in part, that an a helix makes optimal use of internal hydrogen bonds. The structure is stabilized by a hydrogen bond between the hydrogen atom attached to the electronegative nitrogen atom of a peptide linkage and the electronegative carbonyl oxygen atom of the fourth amino acid on the amino-terminal side of that peptide bond (Fig. 4-4b). Within the a helix, every peptide bond (except those close to each end of the helix) participates in such hydrogen bonding. Each successive turn of the a helix is held to adjacent turns by three to four hydrogen bonds. All the hydrogen bonds combined give the entire helical structure considerable stability.

Further model-building experiments have shown that an a helix can form in polypeptides consisting of either l- or d-amino acids. However, all residues must be of one stereoisomeric series; a d-amino acid will disrupt a regular structure consisting of l-amino acids, and vice versa. Naturally occurring l-amino acids can form either right- or left-handed a helices, but extended left-handed helices have not been observed in proteins.

Linus Paquling Nobel Peace Prize
Linus Pauling, 1901-1994

Amino terminus

Amino terminus

Q Carbon O Hydrogen QOxygen O Nitrogen Q R group

Carboxyl terminus (a)

FIGURE 4-4 Four models of the a helix, showing different aspects of its structure. (a) Formation of a right-handed a helix. The planes of the rigid peptide bonds are parallel to the long axis of the helix, depicted here as a vertical rod. (b) Ball-and-stick model of a right-handed a helix, showing the intrachain hydrogen bonds. The repeat unit is a single turn of the helix, 3.6 residues. (c)The a helix as viewed from one end, looking down the longitudinal axis (derived from PDB

Q Carbon O Hydrogen QOxygen O Nitrogen Q R group

ID 4TNC). Note the positions of the R groups, represented by purple spheres. This ball-and-stick model, used to emphasize the helical arrangement, gives the false impression that the helix is hollow, because the balls do not represent the van der Waals radii of the individual atoms. As the space-filling model (d) shows, the atoms in the center of the a helix are in very close contact.

Amino Acid Sequence Affects a Helix Stability

Not all polypeptides can form a stable a helix. Interactions between amino acid side chains can stabilize or destabilize this structure. For example, if a polypeptide chain has a long block of Glu residues, this segment of the chain will not form an a helix at pH 7.0. The negatively charged carboxyl groups of adjacent Glu residues repel each other so strongly that they prevent formation of the a helix. For the same reason, if there are many adjacent Lys and/or Arg residues, which have positively charged R groups at pH 7.0, they will also repel each other and prevent formation of the a helix. The bulk and shape of Asn, Ser, Thr, and Cys residues can also destabilize an a helix if they are close together in the chain.

The twist of an a helix ensures that critical interactions occur between an amino acid side chain and the side chain three (and sometimes four) residues away on either side of it (Fig. 4-5). Positively charged amino acids are often found three residues away from negatively charged amino acids, permitting the formation of an ion pair. Two aromatic amino acid residues are often similarly spaced, resulting in a hydrophobic interaction.

FIGURE 4-5 Interactions between R groups of amino acids three residues apart in an a helix. An ionic interaction between Asp100 and Arg103 in an a-helical region of the protein troponin C, a calcium-binding protein associated with muscle, is shown in this space-filling model (derived from PDB ID 4TNC). The polypeptide backbone (carbons, a-amino nitrogens, and a-carbonyl oxygens) is shown in gray for a helix segment 13 residues long. The only side chains represented here are the interacting Asp (red) and Arg (blue) side chains.

FIGURE 4-5 Interactions between R groups of amino acids three residues apart in an a helix. An ionic interaction between Asp100 and Arg103 in an a-helical region of the protein troponin C, a calcium-binding protein associated with muscle, is shown in this space-filling model (derived from PDB ID 4TNC). The polypeptide backbone (carbons, a-amino nitrogens, and a-carbonyl oxygens) is shown in gray for a helix segment 13 residues long. The only side chains represented here are the interacting Asp (red) and Arg (blue) side chains.

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