Principles of Biochemistry/Proteins-DNA Specificity

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Protein-DNA specificity can be categorized into two main categories: Base readout (proteins that are able to recognize DNA bases) and shape readout (proteins that are able to recognize DNA shape). These two categories are further divided into other sub-categories. For Base Readout, there are interactions in the major and minor grooves. Interactions in the minor groove are composed of hydrogen bonding and hydrophobic effects. Interactions in the major groove are composed of hydrogen bonding and hydrophobic interactions as well as water-mediated interactions. I added the sentence saying that: Water-mediated interactions are only useful in base readout for the major grooves of DNA because they indicate proton donors and acceptors within the groove. However, these water-mediated interactions are useless for base readout in the minor groove because they become unrecognizable in its narrow depths.Global shape recognition can depend on the overall structure of the DNA molecule, taking the form of A-DNA, Z-DNA, or bending within the helix. On the other hand, local shape readout depends on the more localized shape differences such as minor grooves, major grooves, and kinks within the DNA helix.


Protein-DNA Specificity Depends On Shape Readout
Global Shape Local Shape
A-DNA-seen in certain protein complexes under dehydrated conditions Minor Grooves-Narrow and Deep in B-DNA but Wide and Shallow in A-DNA
Z-DNA-Thought to have been created by the supercoiling of B-DNA Major Grooves-Wide and Shallow in B-DNA, but Narrow and Deep in A-DNA
Bending –curving of the DNA helix backbone over several base pairs Kinks- a base pair step is missed in the stacking of the helix backbone


From left to right, a straight B-DNA strand, a bent B-DNA strand, and a kinked B-DNA strand

Protein-DNA Specificity Depends On Base Readout
Minor Groove Major Groove
Patterns for water-mediated interactions become unrecognizable in the minor groove Water-Mediated Interactions- indicate to the availability of proton donors and acceptors
Hydrogen Bonding- repelling of polar molecules from binding site Hydrogen Bonding- repelling of polar molecules from binding site
Hydrophobic Interactions- permits the binding of non-polar substances Hydrophobic Interactions- permits the binding of non-polar substances


Kinks in the DNA strand are stabilized through a process called intercalation in which the DNA strand will become deformed in order to make contact between its phosphate groups. Sometimes there is complete intercalation in which the DNA shape is changed to allow for phosphordiester bonds. However, there is another type of intercalation in which the DNA strand behaves as a binding site. In this case, a protein can bind to the site of the kink and either preserve or further deform the overall shape of the DNA.”

[4] Hydrogen bonds in the major groove allow greater specificity due to the presence of four base pairs and the unique pattern between hydrogen bond donors and hydrogen bond acceptors.

A protein bound to a strand of B-DNA, stabilizing it through intercalation.

Protein can bind to DNA based on the conformation of the strand of DNA in question. The bends, kinks, and overall structure of a strand of DNA allows for the binding of certain proteins. However, the binding of proteins to a strand of DNA often changes the structure of the DNA. The binding of certain proteins can cause bends, kinks, deformations, and intercalations within the DNA strand. The binding of a protein to a section of the DNA may completely change which proteins that stand of DNA can bind to from then on.

Cooperativity is the process by which multiple DNA-binding proteins bind through these processes to make higher order nucleoprotein complexes. These large conglomerates of DNA and protein are capable of undergoing reactions that their individual quaternary selves would not be able to. [5]

Hydrophobic interactions in the major groove play a key role in sequence specific recognition of DNA strand. Hydrophobic interactions allow protein side chains to distinguish between base pairs thymine and cytosine.

The displacement in the minor groove among water molecules due to hydrogen bonding provides a strong thermodynamic driving force for DNA binding.

Factors that contribute to specificity:

  1. Hydrogen Bonds
  2. Hydrophobic interactions
  3. Sequence dependent DNA structures
  4. Deformability of DNA