Opening image: Bacteriorhodopsin. Only the seven transmembrane α-helices are shown. The model also shows six proline residues in CPK colors.
For an unfolded polypeptide in solution, the hydration of the peptide groups and polar side chains allows a large number of floppy, extended conformations to exist. Water, however, is a poor solvent for the nonpolar side chains. Thus, in water there is a strong tendency for the polypeptide chain to fold into a single unique three-dimensional structure, referred to as its tertiary structure.
The fact that water is not a good solvent for nonpolar side chains gives rise to the hydrophobic effect, which makes a major contribution to the folding of water-soluble proteins. The polypeptide chain folds in order to shield as many as possible of its water-insoluble side chains from the solvent. However, many of the polar C=O and N–H of the peptide groups connecting hydrophobic side chains are dragged along as these side chains come together in the interior core, breaking a large number of hydrogen bonds to water. If the broken hydrogen bonds were not replaced by internal hydrogen bonds, the cost of burying the peptide C=O and N–H groups inside the hydrophobic core would be prohibitive. Consequently, at least half of the peptide C=O and N–H groups of globular proteins participate in buried hydrogen bonds.
These internal hydrogen bonds are often arranged in periodic structures called the α-helix and the β-sheet. These secondary structures provide a way to preserve hydrogen bonding of the peptide C=O and N–H in a hydrophobic environment. In addition to providing a way to form hydrogen bonds in the interior of protein, secondary structures also provide a fairly rigid structural framework or scaffolding for the tertiary structure.
A helix is a spiral with a constant radius. The α-helix is the only helical structure in proteins free from steric strain. It is a right-handed helix with 3.6 amino acid residues per turn. Rather than merely describe the α-helix, it is worthwhile to discuss in a general way all the stereochemical requirements for helix formation.
If the conformation of a polypeptide chain is helical, the general direction of the covalent bonds in the chain will be along the axis. Noncovalent interactions will hold successive turns in register one above the other. The main-chain atoms must be close but not too close. Too open a structure would lack van der Waals contacts, but steric crowding or repulsion between lone-pair electrons would destabilize the structure. Hydrogen bonds could allow tighter packing, but tight packing of main-chain atoms requires hydrogen bonding along the general direction of the helix axis. Since the C=O and N–H groups will be the ones involved in hydrogen bonding, the plane of the peptide bond must be roughly parallel to the helix axis also. Finally, there must be room for the side chains. Because of steric factors L-amino acids will form a right-handed helix with all the carbonyl groups pointing toward the C-terminus. A polypetide chain containing only D-amino acids will form a left-handed helix.
The α-helix found in proteins meets all of the design requirements discussed in the introduction. In the α-helix every C=O group is in position for hydrogen bonding with the N–H group four residues away. There are no gaps or empty space inside the helix, since efficient packing of the main-chain atoms takes up 99% of the core. Finally, the side chains project outward from the side of the cylinder formed by the tightly packed backbone.