Proteins fold through a number of different mechanisms, and maintain their shapes through the interaction of different amino acids. The amino acids that proteins are composed of have diverse structures and chemical properties. This gives rise to the ability for proteins to form a range of different types of chemical bonds.

The interactions between amino acids means that proteins can form specific interactions, as interactions will typically take place between pairs or groups of amino acids, differences in composition of the amino acids can affect the ability for different structures to form. However the fact that some amino acids can form different types of interaction allows some flexibility in the protein structure.

Here are the main types of protein interactions, which allow proteins to fold into their finished structures, and to form quaternary structures.

Electrostatic Interactions

The simplest interaction to understand is probably electrostatic interactions. Proteins contain both acidic carboxyl and basic amine groups, which in water lose and gain hydrogen atoms respectively, to form negatively and positively charged chemical groups.

Figure 1: Amino acids which contain amine or carboxyl groups in their in their R groups, such as arginine and aspartic acid (but also lysine and glutamic acid) ionize to form positively and negatively charged groups. Due to the attraction of opposite charges, this causes the amino acids to be attracted to each other to form strong, specific interactions between the amino acids.

Due to their opposite charges, the groups attract each other in a similar way to static electricity. This opposite charge attraction allows a strong bond to form between acidic (glutamic acid and aspartic acid) amino acids and basic (arginine and lysine) amino acids (Figure 1).

Hydrogen Bonds

The hydrogen-oxygen bond has a property that the electrons in the bond are drawn from the hydrogen atom towards the oxygen atom. This isn't to an extent great enough to break the bond, but it is enough to form a charge differential, or dipole, across the bond, with the oxygen atom holding a slightly negative charge (delta-) and the hydrogen atom holding a slightly positive charge (delta+).

Figure 2: The bond between hydrogen and oxygen is between one atom (oxygen) that has a stronger tendency to draw electrons towards it. Because the electrons are negatively charged, this makes the oxygen have a slightly negative charge and the hydrogen have a slightly positive charge, even though it doesn't fully ionize and remains a covalent bond. This charge difference allows amino acids containing oxygen-hydrogen bonds to form interactions through attraction of opposite charges between oxygen and hydrogen atoms.

This has similar effects to the electrostatic interaction, the differences in charge allow the formation of opposite charges, which allows electrostatic bonds to form on a similar basis to those between charged amino acids (Figure 2). Amino acids with the dipole (neutral polar amino acids) can form interactions with any other polar amino acids, whether they are acidic, basic or neutral. This allows neutral polar amino acids to form more generalized interactions with other amino acids than charged amino acids do, which has some impacts on protein flexibility, allowing different protein complexes to form for different purposes.

Sulphur Bridges

Sulphur containing amino acids, especially cysteine have the property of being able to form sulphur bridges. Unlike the other interactions mentioned here, sulphur bridges are covalent bonds, which are strong, rigid bonds that are formed when atoms, in this case sulphur atoms share electrons. These interactions between the sulphur atoms are rigid, and very specific and form strong protein structures (Figure 3).

Figure 3: Amino acids that contain sulphur, such as cysteine can form covalent bonds between the sulphur atoms. These covalent bonds are strong and rigid, unlike the other forces. In creating these bonds, hydrogen atoms are released, which makes this an oxidization reaction, whereas the cell is a reducing environment, so these bonds are not as stable in the intracellular environment, which is a reducing environment.

When sulphur bridges form they release hydrogen atoms (not to be confused with ions, as in electrostatic interactions), as the sulphur-hydrogen bonds are replaced with sulphur-sulphur bonds. As this is a loss of hydrogen atoms, this means that the formation of sulphur bridges is an oxidization reaction. As the intracellular environment is generally a reducing (which adds hydrogen atoms to molecules), this means that sulphur bridges while strong are not very stable in the intracellular solution, as the reducing environment has the tendency to break them.

Van Der Waals Forces

Unlike oxygen-hydrogen bonds that form hydrogen bonds, chains of carbon-carbon and carbon-hydrogen bonds do not innately have a charge differential, as neither of the atoms particularly strongly draw electrons towards them. However because the electrons that form the bonds are somewhat fluid throughout the chain, they can rearrange themselves to form charge differentials. This particularly happens when large chains of carbon-carbon bonds are brought close to each other (Figure 4).

Figure 4: Amino acids with a large number of carbon-carbon bonds can form Van Der Waals forces. Although the electrons are not inherently drawn towards or away from any particular atoms as with hydrogen bonds, the electrons are somewhat fluid throughout the chain of atoms, and the close proximity of the two chains causes electrons to tend to accumulate in some parts of the carbon chain more than others. This uneven distribution of electrons causes charge differences throughout the carbon chain, which promotes the formation of interactions on the basis of opposite charges distributed throughout them.

These induced charges and the bonds between molecules that are formed are called Van Der Waals forces. As they are induced charges, Van Der Waals forces are not as strong as electrostatics, hydrogen bonds, or sulphur bridges, but they allow hydrophobic amino acids which cannot form these types of innately charged interactions to form interactions.

Hydrophobic Shielding

Another type of interaction that hydrophobic amino acids can form, as distinct from Van Der Waals forces is hydrophobic shielding. Hydrophobic regions of proteins repel water, and so a protein will tend to fold in a way that reduces the contact area between hydrophobic amino acids and surrounding water (Figure 5). This generally leaves the hydrophobic residues buried on the inside of protein structures, while polar residues are on the outside.

Figure 5: Hydrophobic amino acids do not like being exposed to water. Because of this, a favourable conformation for the protein to adopt is to bury these hydrophobic residues inside the proteins, away from the water in the surrounding solution.

This tendency for hydrophobic amino acids to avoid water is so strong that it is the driving force behind the formation of protein structures. This drives the formation of single proteins, protein-protein interactions, and especially in interactions between membrane proteins and the phospholipid bilayer.

A similar phenomenon can happen to hydrophilic amino acids which are within hydrophobic regions of proteins. These will have a tendancy to interact with one another, as opposed to the surrounding hydrophobic environment. This similarly drives the formation of particular structural conformations to ensure these amino acids are aligned.