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Bonding and Protein Structure

© David Marcey, 2001

I. Introduction
II. Covalent Bonds - Disulfide Bridges
III. Electrostatic Interactions
IV. Hydrophobic Bonds
V. Van der Waals Forces
VI. References

Note:  This exhibit is best viewed if the cue buttons ( ) are pressed in sequence and if the viewer does not independently manipulate the molecule on the left.

I. Introduction

  This exhibit shows a few examples of the types of chemical bonds that play important roles in stabilizing 3-D protein structure. A model peptide of 12 amino acids (gly193-asn204) that spans the gamma chymotrypsin protein (at left) is used to illustrate example bonds in a known structure. The gamma chymotrypsin protein consists of four peptide chains (A,B,C,D), generated by cleavage of a precursor polypeptide .

Show the model peptide: .

Backbone atoms are violet, sidechain atoms are in the CPK color scheme:
C, H, N, O, P, S

II. Covalent Bonds - Disulfide Bridges

  Covalent bonds are the strongest chemical bonds contributing to protein structure. Covalent bonds arise when two atoms share electrons.

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-- .  A disulfide bridge between cys201 in the model peptide and cys136 is shown here: .


III. Electrostatic Interactions

   A. Ionic Bonds - Salt Bridges
Ionic bonds are formed as amino acids bearing opposite electrical charges are juxtaposed in the hydrophobic core of proteins. Ionic bonding in the interior is rare because most charged amino acids lie on the protein surface. Although rare, ionic bonds can be important to protein structure because they are potent electrostatic attractions that can approach the strength of covalent bonds. 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)

B. Water Shells and Charged Surface Residues
Electrically charged amino acids, mostly found on protein surfaces, promote appropriate folding by interacting with the water solvent. Polar water molecules can form shells around charged surface residue sidechains, helping to stabilize and solubilize the protein. Here, electrostatic interactions between electronegative oxygens of two H2O's and the positively charged NH3's on the sidechains of lys202 and lys203 are shown: .

C. Hydrogen Bonds
When two atoms bearing partial negative charges share a partially positively charged hydrogen, the atoms are engaged in a hydrogen bond (H-bond). 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:

  1. atoms on two different amino acid sidechains
  2. atoms on amino acid sidechains and water molecules at the protein surface
  3. atoms on amino acid sidechains and protein backbone atoms
  4. backbone atoms and water molecules at the protein surface
  5. 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 (hydrogens not shown).

Ser195 in the model peptide is positioned to interact with his57 through a hydrogen bond, its sidechain -O sharing a hydrogen with a nitrogen (N) on the sidechain ring of his57 .

Gly193 provides an H-bond acceptor (its backbone carboxy oxygen) and his40's sidechain provides an -NH donor, forming a hydrogen bond .

Asp204 contains a sidechain 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 backbone N-H and C=O groups in either alpha helices or beta sheets. The model peptide (residues 193-204) is a beta strand that is extensively H-bonded to an adjacent, antiparallel beta strand (residues 205-214). Here, two H-bonds between backbone atoms in leu199 and gly211 are shown .


IV. Hydrophobic Bonds

   Hydrophobic bonds are a major force driving proper protein folding. They juxtapose hydrophobic sidechains by minimizing lost energy caused 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.

Pro198 and val200 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 leu209, val121 , and trp207 are shown here .

Not all hydrophobic amino acids are in the interior of proteins, however. When found at the surface, exposed to polar water molecules, hydrophobic sidechains are usually involved in extensive hydrophobic bonding. Here, hydrophobic bonding between pro24 and phe71 is illustrated .


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. The dots around atoms in this and other displays represent Van der Waals radii.

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 (individual Van der Waals attractions not shown) .

Van der Waals forces can play important roles in protein-protein recognition when complementary shapes are involved. This is the case in antibody-antigen recognition, where a "lock and key" fit of the two molecules yields extensive Van der Waals attractions.

VI. References

  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.


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