Directions This exhibit displays molecules in the left part of the screen,
and text that addresses structure-function relationships of
the molecules in the right part (below). Use the scroll bar
to the right to scroll through the text of this exhibit.
This exhibit shows a few examples of the types of chemical bonds that play important roles in determining and stabilizing 3-D protein structure. For more background on bonds, including strong and weak bonds, see the chemical bonds page.
The gamma chymotrypsin protein, shown at left, will serve as an example protein. It consists of four peptide chains (A,,B,,C,,D), generated by cleavage of a precursor peptide.
A model peptide of 12 amino acids (gly193-asn204) of chain C that spans the protein will be used used to illustrate example bonds in a known structure. Backbone atoms are pink and sidechain atoms are in the CPK color scheme: C, H, N, O, P, S (hydrogens not shown). As will be seen, most residues of this peptide are contained in a β-strand. Note that the part of the peptide that spans the interior of the protein comprises multiple amino acids with hydrophobic side chains.
II. Covalent Bonds- Disulfide Bridges
Covalent bonds are the strongest chemical bonds contributing to protein structure. A covalent bond arises when two atoms share a pair of electrons. For more background on covalent bonds, see the covalent bonds page.
In addition to the covalent bonds that connect the atoms of a single amino acid and the covalent peptide bond that links amino acids in a protein chain, covalent bonds between cysteine side chains can be important determinants of protein structure. Cysteine is the sole amino acid whose side chain can form covalent bonds, yielding disulfide bridges with other cysteine side chains: --CH2-S-S-CH2--. Here, cysteine 201 of the model peptide is seen to be covalently bonded with cysteine 136 from an adjacent β-strand.
III. Electrostatic Interactions
Ionic Bonds (salt bridges)
Ionic bonds are formed as atoms of amino acids bearing opposite electrical charges are juxtaposed. Ionic bonds can be important to protein structure because they are potent electrostatic attractions. In the hydrophobic interior of proteins, ionic bonds can even approach the strength of covalent bonds. For more background on ionic bonds, see the ionic bonds page.
In the model peptide, a negatively charged O on the sidechain of asp194 lies 2.8 Å from the positively charged N on the amino terminus of chain B (ile16), and these atoms engage in an ionic bond (salt bridge).
When two atoms bearing partial negative charges share a partially positively charged hydrogen, the atoms are engaged in a hydrogen bond (H-bond). H-bonds vary in length but are typically in the 1.5-2.5 Å range. For more background on hydrogen bonds, see the hydrogen bonds page.
The correct 3-D structure of a protein is often dependent on an intricate network of H-bonds. These can occur between a variety of atoms, involving:
- atoms on two different amino acid sidechains
- atoms on amino acid sidechains and protein backbone atoms
- atoms on amino acid sidechains and water molecules at the protein surface
- backbone atoms and water molecules at the protein surface
- backbone atoms on two different amino acids
Examples of several of these types of H-bonds may be illustrated using amino acids of the model peptide.
Seen here, an H-bond donor (O) on the sidechain of serine 195 and its corresponding H-bond acceptor (N) on the sidechain of histidine 57 "share" a partially charged hydrogen.
- Glycine 193 provides an H-bond acceptor (its backbone carbonyl O) and histidine 40's sidechain provides an -NH donor, forming a hydrogen bond .
- Asparagine 204 contains a backbone carbonyl group (C=O) group that can accept a hydrogen from a solvent H2O at the protein surface.
- Most of the H-bonds in a protein are between main chain (backbone) N-H and C=O groups in either alpha helices or beta sheets. Most of the model peptide (residues 193-203) is a beta strand that is extensively H-bonded to an adjacent, antiparallel beta strand (residues 206-214). Here, two H-bonds between backbone atoms in leucine 199 and glycine 211 are shown.
C. Water Shells and Polar Surface Residues
Polar amino acids, mostly found on protein surfaces, promote appropriate folding by interacting with the water solvent. Polar water molecules can form shells around charged or partially charged surface residue atoms, helping to stabilize and solubilize the protein.
Here you can see H-bonds between an H2O oxygen and a sidechain OH of serine 217 and between an H2O hydrogen and the carbonyl O of serine 223.
Another example is an H-bond between an H2O hydrogen and the sidechin O of glutamine 240.
Only a fraction of the water molecules that surround a protein in vivo are visualized in the chymotrypsin crystal structure of this exhibit (PDB ID 1AB9). These can be seen interacting with the protein surface.
IV. Hydrophobic Interactions
Hydrophobic interactions ("bonds") are a major force driving proper protein folding. They juxtapose hydrophobic sidechains by reducing the energy generated by the intrusion of amino acids into the H2O solvent, which disrupts lattices of water molecules. Hydrophobic bonding forms an interior, hydrophobic, protein core, where most hydrophobic sidechains can closely associate and are shielded from interactions with solvent H2O's. For more information on these interactions, see the hydrophobic bonds page.
Proline 198 and valine 200 are two of six, interior, hydrophobic amino acids in the model peptide. The close association of the hydrocarbon sidechains of these aa's and those of leucine 209, valine 121, and tryptophan 207 are shown here.
Not all hydrophobic amino acids are in the interior of proteins, however. When found at the surface, exposed to polar H2O molecules, hydrophobic sidechains are usually involved in extensive hydrophobic bonding. Here, packing of the hydrophobic sidechains of proline 24 and phenylalanine 71 is observed.
V. Van der Waals Forces
The Van der Waals force is a transient, weak electrical attraction of one atom for another. Van der Waals attractions exist because every atom has an electron cloud that can fluctuate, yielding a temporary electric dipole. The transient dipole in one atom can induce a complementary dipole in another atom, provided the two atoms are quite close. These short-lived, complementary dipoles provide a weak electrostatic attraction, the Van der Waals force. Of course, if the two electron clouds of adjacent atoms are too close, repulsive forces come into play because of the negatively-charged electrons. The appropriate distance required for Van der Waals attractions differs from atom to atom, based on the size of each electron cloud, and is referred to as the Van der Waals radius. When atoms are rendered in spacefill in this or other exhibits, the spacefill diameter is 2x the Van der Waals radius.Van der Waals attractions, although transient and weak, can provide an important component of protein structure because of their sheer number. Most atoms of a protein are packed sufficiently close to others to be involved in transient Van der Waals attractions. This can be seen in the case of the model peptide, embedded in the dense interior of the chymotrypsin protein (individual Van der Waals attractions not shown).
Van der Waals forces can play important roles in protein-protein recognition when complementary shapes are involved. An example is the case of antibody-antigen recognition, where a complementary fit of the two interacting molecules across a broad surface yields extensive Van der Waals attractions.
Brandon, C., and J. Tooze, Introduction to Protein Structure. Garland Publishing, New York/London, 1991.
Dressler, D., and H. Potter, Discovering Enzymes. W.H. Freeman, New York/Oxford, 1991.
N.H.Yennawar, H.P.Yennawar, G.K. Farber (1994) X-ray Crystal Structure of Gamma-chymotrypsin in Hexane. Biochemistry 33: 7326.
M.Harel, C.T.Su, F.Frolow, I.Silman, J.L.Sussman (1991) Gamma-chymotrypsin Is a Complex of Alpha-chymotrypsin with its Own Autolysis Products. Biochemistry 30: 5217.