Understanding the Structures of Proteins

Proteins are large biological molecules made of amino acid chains held together by different types of bonds. These bonds form a unique three-dimensional shape called a protein’s conformation.


The sequence of linear amino acid chains determines a protein’s primary structure. Hydrogen bonding between amino groups and carboxyl groups causes the chain to fold into stable patterns such as a-helix or beta pleated sheets.

Primary Structure

The primary structure of a protein is the particular sequence of amino acid residues that make up the polypeptide chain. It is the result of the condensation of amino acids into a three-dimensional shape driven by the specific interactions of local, low-energy chemical bonds between stretches of the protein backbone and the side chains of its amino acid residues.

The next level of protein structure is the secondary structure. It refers to the local folded structures that form within the polypeptide backbone due to interactions between atoms of the backbone itself. These include the a helix and b pleated sheet shapes. Both of these structures are held together by hydrogen bonds between the carbonyl oxygen and the amino hydrogen of one or more adjacent residues.

Alpha helixes are formed by two consecutive amino acid residues and beta strands by four successive amino acids. These amino acid side chains may have polar or non-polar functional groups that interact with the surrounding water molecules and can contribute to the stability of the protein.

Some proteins have gamma turns, which are unstructured regions that occur between regular secondary structure elements. These turns are often involved in connecting two a helices or beta strands together. They involve a single peptide residue forming a hydrogen bond between the C=O of the peptide group and the N-H of the peptide group of the corresponding residue four residues earlier in the chain.

Secondary Structure

The secondary structure of a protein is the regular local arrangement of segments of the polypeptide chain, stabilized by hydrogen bonding between the -CO and -NH groups of adjacent amino acid residues. Alpha-helix and beta-pleated sheets are the two most common forms of protein secondary structures. This structure is determined mainly by the amino acid sequence, with those having bulky side chains tending to form b-sheets and those without preferring alpha-helix formation.

The tertiary structure of a protein is the final 3-D shape formed by folding of the protein’s secondary structure into a global conformation. The tertiary structure is further stabilized by nonlocal interactions such as hydrophobic bonds, salt bridges and disulfide bonds.

Accurate prediction of tertiary structure is difficult, although it appears that the main area where improvements could be made lies in correctly predicting the position and type of b-strands, which are a common feature of proteins. It is currently believed that protein b-strands are primarily created by hydrogen bonding between the -NH group of an amino acid and the -CO of an amino acid two residues ahead of it in the sequence. This interaction is not easily accommodated by current protein secondary-structure prediction methods which tend to overestimate the number of b-strands and underestimate the lengths of b-strand segments (false negatives). The result is that the most confidently predicted b-strand positions are not necessarily the correct ones.

Tertiary Structure

The tertiary structure is the overall three-dimensional arrangement of the protein in space. It is determined by the weak interactions that form between amino acid side chains. These interactions give rise to alpha helixes, beta sheets and other local structures called secondary structures. The tertiary structure is responsible for the folding of the proteins into their native shapes and it allows the protein to interact with other molecules such as ligands and cofactors.

When a protein folds either as it is being made on ribosomes or after it has been purified, the first step involves nucleating secondary structural elements from hydrogen bonds formed by amide hydrogen atoms with carbonyl oxygens (see Figure below). The alpha helix and the beta sheet are two of the most common types of secondary structures in proteins.

Alpha helixes consist of amino acid side chains arranged in a spiral. As shown in the Kinemage link below, a single alpha helix can be viewed with all atoms colored cyan and a view with only the hydrogen atoms colored brown.

Alpha helixes are often stabilized by hydrophobic interactions that cause the nonpolar amino acid residues to “bury” themselves inside the protein with the water molecules. In some cases, the interaction between polar amino acid residues can take the form of salt bridges that bring a positive side chain, such as Arg, close to a negative side chain, such as Gly or Asp.

Quaternary Structure

The quaternary structure of a protein is the overall shape that it takes, which is determined by the location and spacing of different secondary structures. It also determines the interactions between proteins, which are critical for many of their functions. Proteins with a quaternary structure are able to form large complexes, which are more functionally important than individual polypeptide chains.

A quaternary structure is formed by the interaction of a protein’s individual polypeptide chains, which are typically bonded to each other via hydrogen bonds and van der Waals forces. The interaction between these chains leads to the formation of secondary structures, such as a helix and a pleated sheet. These secondary structures are held in place by hydrogen bonding between the carbonyl O of one polypeptide chain and the amino H of another.

The interactions between these chains also lead to the creation of a tertiary structure, which is determined by how different segments of a protein are positioned relative to each other. The tertiary structure is often stabilised by nonlocal interactions, such as salt bridges, hydrogen bonds, disulfide bonds or posttranslational modifications.

These interactions are necessary to ensure that a protein’s three-dimensional structure is maintained in a biologically relevant manner. When a protein loses its tertiary structure, it becomes denatured and is no longer functional. For example, the quaternary structure of hemoglobin is what allows it to bind oxygen molecules.