Amino Acids and Protein Structure (Video)

0:14 From a chain to a shape

First, we will go from a chain to a shape. A ribosome makes a protein as a linear chain of amino acids. The chain then folds into a working protein. The first three-dimensional structure of a protein came from John Kendrew and his colleagues in 1958. They solved sperm whale myoglobin by X-ray crystallography. Max Perutz solved hemoglobin soon after, and the two shared the 1962 Nobel Prize in Chemistry. The structure showed that a protein chain folds into a compact and specific shape.

0:59 The amino acid

Second, we will look at the amino acid. The shape of a protein follows from the amino acids in its chain. Each amino acid has a central carbon, the alpha carbon, bonded to an amino group, a carboxyl group, a hydrogen atom and a side chain, the R group. At pH 7.4, the amino group carries a positive charge and the carboxyl group a negative charge. Proteins use 20 standard amino acids, and they differ only in their side chains. The side chains fall into groups by their chemistry. Nonpolar side chains such as leucine and valine avoid water, and polar side chains such as serine form hydrogen bonds. Acidic side chains such as aspartate carry a negative charge, and basic side chains such as lysine carry a positive charge. Glycine has a single hydrogen atom as its side chain, and proline bonds back to its own amino group, which makes the chain kink.

1:56 The peptide bond and primary structure

Third, we will cover the peptide bond and primary structure. Amino acids join into a chain through peptide bonds. A peptide bond forms between the carboxyl group of one amino acid and the amino group of the next, and one water molecule leaves. If you follow the backbone, you see nitrogen, alpha carbon and carbonyl units repeating. The chain ends with a free amino group at the N-terminus and a free carboxyl group at the C-terminus. The peptide bond has partial double-bond character, so it is planar and does not rotate. The chain bends only at the bonds either side of each alpha carbon. Primary structure is the sequence of amino acids from the N-terminus to the C-terminus. Between 1951 and 1955, Frederick Sanger determined the sequence of insulin, the first protein sequenced.

2:47 Secondary structure

The fourth part covers secondary structure. Once the chain exists, the first folding happens locally. Secondary structure is local folding held by hydrogen bonds between backbone atoms. A residue is one amino acid in the chain. In each of these hydrogen bonds, the carbonyl oxygen of one residue bonds to the amide hydrogen of another. In 1951, Linus Pauling, Robert Corey and Herman Branson proposed the alpha helix. It is right-handed, with 3.6 residues per turn, and the carbonyl oxygen of each residue bonds to the amide hydrogen of the residue four positions further along the chain. The side chains point outward from the helix. Strands form the second common secondary structure, the beta sheet, in which extended strands lie side by side and hydrogen bonds form between neighboring strands. The strands run in the same direction, giving a parallel sheet, or in opposite directions, giving an antiparallel sheet. Turns and loops connect helices and strands.

3:50 Tertiary and quaternary structure

Fifth, we will look at tertiary and quaternary structure. The whole chain then packs into one shape. Tertiary structure is the full three-dimensional fold of one polypeptide chain. Interactions between side chains hold that fold in place. The hydrophobic effect, the tendency of nonpolar groups to avoid water, drives the fold. Nonpolar side chains sit in the core, and polar side chains face the surface. Hydrogen bonds, ionic bonds between oppositely charged side chains, and disulfide bonds between cysteines also stabilize the fold. Many proteins contain more than one chain. Quaternary structure is the arrangement of two or more polypeptide chains in one protein. Hemoglobin has four chains, two alpha and two beta, and each holds one heme group.

4:39 Sequence decides shape

The last part shows how the sequence decides the shape. If the sequence decides the shape, an unfolded protein should fold again by itself. Christian Anfinsen tested that prediction with the enzyme ribonuclease A in the late 1950s and early 1960s. He unfolded the enzyme with urea and a reducing agent, which broke its four disulfide bonds and abolished its activity. When he removed the urea and the reducing agent slowly, the enzyme refolded and recovered almost all of its activity. The information for the fold therefore lies in the amino acid sequence. Anfinsen shared the 1972 Nobel Prize in Chemistry for this work. A single change in sequence can change how a protein behaves. In sickle cell disease, valine replaces glutamate at position 6 of the beta chain of hemoglobin, and the molecules stick together into long fibers when oxygen is low. Here is a short review of the main points. Peptide bonds join amino acids into a chain, and the order of those amino acids is the primary structure. Hydrogen bonds between backbone atoms fold the chain locally into alpha helices and beta sheets, and interactions between side chains pack the chain into its tertiary fold. Anfinsen's experiment showed that the amino acid sequence carries the information for that fold. Test what you learned with this question. Why does the hydrophobic effect place nonpolar side chains in the core of a folded protein? Take a moment to work it out, then compare with the answer. Nonpolar side chains cannot form hydrogen bonds with water, so water molecules form ordered shells around these side chains. Burying the side chains in the core releases the ordered water and increases its entropy, which stabilizes the folded state.