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When we talked about hydrogen bonds and their role in protein folding, weconcluded that hydrogen bonds would not contribute much to the stability of thefolded state. The reason was that, for every intra-molecular hydrogen bond weform during protein folding , we have to disrupt a hydrogen bond between theprotein and the solvent.

I the case of DNA it turns out that hydrogen bonds do indeed stabilize theinteraction between bases.The difference is in the nature of the hydrogen bonds.

First, Watson-Crick base pairing involves at least one pair of mutuallyreinforcing hydrogen bonds (see next slide). As we learned earlier, thesehydrogen bonds are substantially stronger than regular hydrogen bonds. Inother words, DNA “ folding” involves the disruption of “ normal” hydrogenbonds and the formation of “ special” hydrogen bonds resulting in a netcontribution to stability.

Second, in the case of the GC basepair, the formation of the “ special pair” ofhydrogen bonds places another donor-acceptor pair so that they are perfectlyoriented for a hydrogen bond. As a result this hydrogen bond can be formedwithout any entropic penalty and it therefore favorable compared to a hydrogenbond with solvent.

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The hydrogen bonds in Watson Crick basepairs are mutually reinforcing.Formation of the first hydrogen bond polarizes the partners of the secondhydrogen bond and vice versa.

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There are 28 different ways to form BasepairsWith two cyclic hydrogen bonds

From:Wolfram Saenger, Principles of Nucleic Acid Structure,Springer advanced texts in chemistry, (1983)

The DNA bases can form many stable hydrogen bonding arrangements. TheWatson-Crick arrangement is just one of them. What makes the Watson-Crickarrangement so special is that this hydrogen bonding arrangement places thebase-to-sugar bonds into a configuration that is compatible with forming acontinuous anti-parallel double helix.

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Here are the cpk models of A-form B-form and Z-form DNA. The detailedmolecular geometry of these helixes is quite different, but they all agree with thebasic rules of DNA structure. The backbones are placed far apart, the bases arenicely stacked and we see perfect hydrogen-bonding geometry.

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The DNA double helix does not have to be disrupted to allow proteins to “ read”the base sequence.In particular, the hydrogen bonding pattern that different basepairs present tothe major groove allows the unique identification of that base pair.

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Here is a schematic picture of a DNA helix together with the alpha helix from atranscription factor. Notice how the protein alpha helix fits perfectly into themajor groove and positions the protein sidechains such that they can “ read” thebase sequence.

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Here is another picture of a transcription factor protein and how it positions itshelices into the major groove.

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Here is the leucine zipper, that we saw earlier in the class when we talked abouthelix-helix interactions in proteins.This helix-helix arrangement aligns the N-terminal helix of these proteins forperfect interactions with the DNA’s major groove.

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The binding of proteins to DNA illustrates the extraordinary conformationalflexibility of DNA. Shown here is the interaction between the TATA-boxbinding protein and its cognate DNA.

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Here is the picture of the DNA in the configuration it adopts when bound to theprotein. See the dramatic 90 degree bend.Still, the DNA geometry full-fills our three criteria for a stable DNA structure:The bases are stacked, the bases hydrogen bond to one another and thebackbones are widely separated.

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While DNA’s usually form relatively boring double helices, RNA molecules,lacking a complementary strand, can form very interesting and stable structuresthat are every bit as “ sophisticated” as protein structures. Ribozymes like thehammerhead ribozyme shown above in a schematic drawing are a good exampleof RNA molecules that operate on the same sequence-determines-structure-determine function paradigm we have seen for proteins.

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Here is the three-dimensional structure of the ribozyme from the previous slide.Notice how most of the structure is in a double-helix-like conformation. Alsonotice the stacking of basepairs in the hammerhaed motif. The bases are stackedeven though they do not hydrogen bond with another strand.

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This is a picture of the 3D crystal structure of a ribosome. The RNA is shown inpink. As you can see much of the RNA is in double-helix-like conformation.The protein is shown in purple. It is quite striking to see, how much the structureis dominated by RNA. Also, virtually all of the chemistry carried out by theribosome is performed by the RNA and not by the protein components makingthe ribosome a true RNA-based macromolecular machine.