D26.5 Protein Denaturation

As we have just discussed, the primary forces that stabilize a protein’s three-dimensional structure are:

  • Sequestration of hydrophobic side chains away from water (for example, in the interior of water-soluble proteins)
  • Maximizing London dispersion interactions (minimizing open spaces) in the interior of proteins
  • Maximizing hydrogen bonding (for example, in α-helices or β-sheets)
  • Attractions between negatively and positively charged sites formed when acidic and basic side chains lose and gain H+ ions

However, the exact process of protein folding is still a very active area of research in chemistry and biochemistry. The first hint came from the work of Christian Anfinsen on the protein ribonuclease, which breaks down RNA molecules. Anfinsen discovered that after treating ribonuclease with high concentrations of certain chemicals that cause proteins to unfold and lose their tertiary and secondary structure, the ribonuclease no longer broke down RNA. Moreover, if the chemicals were removed, the ribonuclease would spontaneously recover nearly all its RNA-hydrolyzing activity, without needing any other cellular components. Anfinsen concluded that the primary structure of a protein completely determines its three-dimensional structure at the secondary, tertiary, and quaternary levels (this is known as Anfinsen’s dogma). However, protein folding in cell is likely to be more complex than that.

The process that Anfinsen used is called denaturation, in which a protein’s native quaternary, tertiary, and/or secondary structure is changed. Proteins can be denatured by application of some external stress or compound, such as pH changes, heavy metal ions, solvent changes, radiation, or heat. All of these disrupt the multitude of noncovalent interactions present in the 3D structure of protein. Denatured proteins can exhibit a wide range of characteristics, from conformational change and loss of solubility to aggregation due to the exposure of hydrophobic groups.

Protein folding is key to whether a protein can do its job correctly; it must be folded into the right shape to function. However, noncovalent interactions, which play a big part in folding, are individually weak, especially compared to covalent bonds. Therefore, they can be relatively easily affected by heat, acidity, varying salt concentrations, and other stresses. This is one reason why a constant physical and chemical environment is physiologically necessary in many life forms.

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