Box 41 Working In Biochemistry

Knowing the Right Hand from the Left

There is a simple method for determining whether a helical structure is right-handed or left-handed. Make fists of your two hands with thumbs outstretched and pointing straight up. Looking at your right hand, think of a helix spiralling up your right thumb in the direction in which the other four fingers are curled as shown (counterclockwise). The resulting helix is right-handed. Your left hand will demonstrate a left-handed helix, which rotates in the clockwise direction as it spirals up your thumb.

A constraint on the formation of the a helix is the presence of Pro or Gly residues. In proline, the nitrogen atom is part of a rigid ring (see Fig. 4-8b), and rotation about the N—Ca bond is not possible. Thus, a Pro residue introduces a destabilizing kink in an a helix. In addition, the nitrogen atom of a Pro residue in peptide linkage has no substituent hydrogen to participate in hydrogen bonds with other residues. For these reasons, proline is only rarely found within an a helix. Glycine occurs infrequently in a helices for a different reason: it has more conformational flexibility than the other amino acid residues. Polymers of glycine tend to take up coiled structures quite different from an a helix.

A final factor affecting the stability of an a helix in a polypeptide is the identity of the amino acid residues near the ends of the a-helical segment. A small electric dipole exists in each peptide bond (Fig. 4-2a). These dipoles are connected through the hydrogen bonds of the helix, resulting in a net dipole extending along the helix that increases with helix length (Fig. 4-6). The four amino acid residues at each end of the helix do not participate fully in the helix hydrogen bonds. The partial positive and negative charges of the helix dipole actually reside on the peptide amino and carbonyl groups near the amino-terminal and carboxyl-terminal ends of the helix, respectively. For this reason, negatively charged amino acids are often found near the amino terminus of the helical segment, where they have a stabilizing interaction with the positive charge of the helix dipole; a positively charged amino acid at the amino-terminal end is destabilizing. The opposite is true at the carboxyl-terminal end of the helical segment.

Thus, five different kinds of constraints affect the stability of an a helix: (1) the electrostatic repulsion (or attraction) between successive amino acid residues with charged R groups, (2) the bulkiness of adjacent R groups, (3) the interactions between R groups spaced three (or four) residues apart, (4) the occurrence of Pro and Gly residues, and (5) the interaction between amino acid residues at the ends of the helical segment and the electric dipole inherent to the a helix. The tendency of a given segment of a polypeptide chain to fold up as an a helix therefore depends on the identity and sequence of amino acid residues within the segment.

Amino terminus

Amino terminus

FIGURE 4-6 Helix dipole. The electric dipole of a peptide bond (see Fig. 4-2a) is transmitted along an a-helical segment through the in-trachain hydrogen bonds, resulting in an overall helix dipole. In this illustration, the amino and carbonyl constituents of each peptide bond are indicated by + and — symbols, respectively. Non-hydrogen-bonded amino and carbonyl constituents in the peptide bonds near each end of the a-helical region are shown in red.

The p Conformation Organizes Polypeptide Chains into Sheets

^ Protein Architecture—p Sheet Pauling and Corey predicted a second type of repetitive structure, the p conformation. This is a more extended conformation of polypeptide chains, and its structure has been confirmed by x-ray analysis. In the 3 conformation, the backbone of the polypeptide chain is extended into a zigzag rather than helical structure (Fig. 4-7). The zigzag polypep-tide chains can be arranged side by side to form a structure resembling a series of pleats. In this arrangement, called a p sheet, hydrogen bonds are formed between adjacent segments of polypeptide chain. The individual segments that form a 3 sheet are usually nearby on the polypeptide chain, but can also be quite distant from each other in the linear sequence of the polypeptide; they may even be segments in different polypeptide chains. The R groups of adjacent amino acids protrude from the zigzag structure in opposite directions, creating the alternating pattern seen in the side views in Figure 4-7.

The adjacent polypeptide chains in a 3 sheet can be either parallel or antiparallel (having the same or opposite amino-to-carboxyl orientations, respectively). The structures are somewhat similar, although the repeat period is shorter for the parallel conformation (6.5 A, versus 7 A for antiparallel) and the hydrogen-bonding patterns are different.

Some protein structures limit the kinds of amino acids that can occur in the 3 sheet. When two or more 3 sheets are layered close together within a protein, the R groups of the amino acid residues on the touching surfaces must be relatively small. ¡-Keratins such as silk fibroin and the fibroin of spider webs have a very high content of Gly and Ala residues, the two amino acids with the smallest R groups. Indeed, in silk fibroin Gly and Ala alternate over large parts of the sequence.

p Turns Are Common in Proteins

^ Protein Architecture—p Turn In globular proteins, which have a compact folded structure, nearly one-third of the amino acid residues are in turns or loops where the polypeptide chain reverses direction (Fig. 4-8). These are the connecting elements that link successive runs of a helix or 3 conformation. Particularly common are p turns that connect the ends of two adjacent segments of an antiparallel 3 sheet. The structure is a 180° turn involving four amino acid residues, with the carbonyl oxygen of the first residue forming a hydrogen bond with the amino-group hydrogen of the fourth. The peptide groups of the central two residues do not participate in any interresidue hydrogen bonding. Gly and Pro residues often occur in 3 turns, the former because it is small and flexible, the latter because peptide bonds

(a) Antiparallel

Top view

Side view

(b) Parallel

Top view

Side view

Top view

Top view

Side view

FIGURE 4-7 The p conformation of polypeptide chains. These top and side views reveal the R groups extending out from the 3 sheet and emphasize the pleated shape described by the planes of the peptide bonds. (An alternative name for this structure is 3-pleated sheet.) Hydrogen-bond cross-links between adjacent chains are also shown. (a) Antiparallel 3 sheet, in which the amino-terminal to carboxyl-terminal orientation of adjacent chains (arrows) is inverse. (b) Parallel 3 sheet.

Side view

FIGURE 4-7 The p conformation of polypeptide chains. These top and side views reveal the R groups extending out from the 3 sheet and emphasize the pleated shape described by the planes of the peptide bonds. (An alternative name for this structure is 3-pleated sheet.) Hydrogen-bond cross-links between adjacent chains are also shown. (a) Antiparallel 3 sheet, in which the amino-terminal to carboxyl-terminal orientation of adjacent chains (arrows) is inverse. (b) Parallel 3 sheet.

involving the imino nitrogen of proline readily assume the cis configuration (Fig. 4-8b), a form that is particularly amenable to a tight turn. Of the several types of 3 turns, the two shown in Figure 4-8a are the most common. Beta turns are often found near the surface of a protein, where the peptide groups of the central two amino acid residues in the turn can hydrogen-bond with water. Considerably less common is the y turn, a three-residue turn with a hydrogen bond between the first and third residues.

Type I

FIGURE 4-8 Structures of fi turns. (a) Type I and type II fi turns are most common; type I turns occur more than twice as frequently as type II. Type II fi turns always have Gly as the third residue. Note the hydrogen bond between the peptide groups of the first and fourth residues of the bends. (Individual amino acid residues are framed by large blue circles.) (b) The trans and cis isomers of a peptide bond involving the imino nitrogen of proline. Of the peptide bonds between amino acid residues other than Pro, over 99.95% are in the trans configuration. For peptide bonds involving the imino nitrogen of proline, however, about 6% are in the cis configuration; many of these occur at fi turns.

Type II

Type I

Type II

FIGURE 4-8 Structures of fi turns. (a) Type I and type II fi turns are most common; type I turns occur more than twice as frequently as type II. Type II fi turns always have Gly as the third residue. Note the hydrogen bond between the peptide groups of the first and fourth residues of the bends. (Individual amino acid residues are framed by large blue circles.) (b) The trans and cis isomers of a peptide bond involving the imino nitrogen of proline. Of the peptide bonds between amino acid residues other than Pro, over 99.95% are in the trans configuration. For peptide bonds involving the imino nitrogen of proline, however, about 6% are in the cis configuration; many of these occur at fi turns.

(b) Proline isomers R ^H

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