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8.1: Nucleic Acid Structure

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  • 4.1 The Structure of DNA and RNA

    Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life. The nucleic acids consists of two major macromolecules, Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) that carry the genetic instructions for the development, functioning, growth and reproduction of all known organisms and viruses. The DNA macromolecule (Figure 4.1) is composed of two polynucleotide chains that coil around each other to form a double helix. The RNA macromolecule usually exists as a single polynucleotide chain that is much shorter than the comparative DNA molecule.

    Figure 4.1: The structure of the DNA double helix. The atoms in the structure are color-coded by element and the detailed structures of two base pairs are shown in the bottom right.

    Image on the left by: Zephyris

    DNA Animation on the right by: brian0918&#153

    The core structure of a nucleic acid monomer is the nucleoside, which consists of a sugar residue + a nitrogenous base that is attached to the sugar residue at the 1′ position (Figure 4.2). The sugar utilized for RNA monomers is ribose, whereas DNA monomers utilize deoxyribose that has lost the hydroxyl functional group at the 2′ position of ribose. For the DNA molecule, there are four nitrogenous bases that are incorporated into the standard DNA structure. These include the Purines: Adenine (A) and Guanine (G), and the Pyrimidines: Cytosine (C) and Thymine (T). RNA uses the same nitrogenous bases as DNA, except for Thymine. Thymine is replaced with Uracil (U) in the RNA structure.

    When one or more phosphate groups are attached to a nucleoside at the 5′ position of the sugar residue, it is called a nucleotide. Nucleotides come in three flavors depending how many phosphates are included: the incorporation of one phosphate forms a nucleoside monophosphate, the incorporation of two phosphates forms a nucleoside diphosphate, and the incorporation of three phosphates forms a nucleoside triphosphate (Figure 4.2).

    Figure 4.2 The Monomer Building Blocks of Nucleic Acids. The site of the nitrogenous base attachment to the sugar residue (glycosidic bond) is shown in red.

    The double helix formed during DNA synthesis has several key physical properties (Figure 4.3). DNA is assembled such that nucleoside monophosphates are incorporated into the growing DNA chains. Unlike the protein α-helix, where the R-groups of the amino acids are positioned to the outside of the helix, in the DNA double helix, the nitrogenous bases are positioned inward and face each other. The backbone of the DNA is made up of repeating sugar-phosphate-sugar-phosphate residues. Bases fit in the double helical model if pyrimidine on one strand is always paired with purine on the other. From Chargaff’s rules, the two strands will pair A with T and G with C. This pairs a keto base with an amino base, a purine with a pyrimidine. Two H‑bonds can form between A and T, and three can form between G and C. This third H-bond in the G:C base pair is between the additional exocyclic amino group on G and the C2 keto group on C. The pyrimidine C2 keto group is not involved in hydrogen bonding in the A:T base pair.

    Furthermore, the orientation of the sugar molecule within the strand determines the directionality of the strands. The phosphate group that makes up part of the nucleotide monomer is always attached to the 5′ position of the deoxyribose sugar residue. The free end that can accept a new incoming nucleotide is the 3′ hydroxyl position of the deoxyribose sugar. Thus, DNA is directional and is always synthesized in the 5′ to 3′ direction. Interestingly, the two strands of the DNA double helix lie in opposite directions or have a head to tail orientation.

    Figure 4.3 Structure of DNA: Lower diagram shows the arrangement of the nucleoside monophosphate within the structure of nucleic acids. In the upper right four nucleotides form two base-pairs: thymine and adenine (connected by double hydrogen bonds) and guanine and cytosine (connected by triple hydrogen bonds). The individual nucleotide monomers are chain-joined at their sugar and phosphate molecules, forming two ‘backbones’ (a double helix) of a nucleic acid, shown at upper left.

    Image modified from: Openstax

    The nucleotide that is required as the monomer for the synthesis of both DNA and RNA is the high energy nucleoside triphosphate. During the incorporation of the nucleotide into the polymeric structure, two phosphate groups, (Pi-Pi , called pyrophosphate) from each triphosphate are cleaved from the incoming nucleotide and further hydrolyzed during the reaction, leaving a nucleoside monophosphate that is incorporated into the growing RNA or DNA chain (Figure 4.4). Incorporation of the incoming nucleoside triphosphate is mediated by the nucleophilic attack of the 3′-OH of the growing DNA polymer. Thus, DNA synthesis is directional, only occuring at the 3′-end of the molecule.

    The further hydolysis of the pyrophosphate (Pi-Pi) releases a large amount of energy ensuring that the overall reaction has a negative ΔG. Hydrolysis of Pi-Pi –> 2Pi has a ΔG = -7 kcal/mol and is essential to provide the overall negative ΔG (-6.5 kcal/mol) of the DNA synthesis reaction. Hydrolysis of the pyrophosphate also ensures that the reverse reaction, pyrophsophorylysis, will not take place removing the newly incorporated nucleotide from the growing DNA chain.

    This reaction is mediated in DNA by a family of enzymes known as DNA polymerases. Similarly, RNA polymerases are required for RNA synthesis. A more detailed description of polymerase reaction mechanisms will be covered in Chapters X and Y, covering DNA Replication and Repair, and DNA Transcription.

    Figure 4.4 Nucleic Acid Synthesis: In nucleic acid synthesis, the 3’ OH of a growing chain of nucleotides attacks the α-phosphate on the next NTP to be incorporated (blue), resulting in a phosphodiester linkage and the release of pyrophosphate (PPi). The DNA polymerase further mediates the hydrolysis of the pyrophosphate preventing the reverse reaction from occurring and releasing enough energy to drive the reaction forward. The synthesis of DNA is shown in this diagram.

    Image modified from Michal Sobkowski

    DNA was first isolated by Friedrich Miescher in 1869. The double-helix model of DNA structure was first published in the journal Nature by James Watson and Francis Crick in 1953,(X,Y,Z coordinates in 1954) based upon the crucial X-ray diffraction image of DNA from Rosalind Franklin in 1952, followed by her more clarified DNA image with Raymond Gosling, Maurice Wilkins, Alexander Stokes, and Herbert Wilson, and base-pairing chemical and biochemical information by Erwin Chargaff. The prior model was triple-stranded DNA.

    The realization that the structure of DNA is that of a double-helix elucidated the mechanism of base pairing by which genetic information is stored and copied in living organisms and is widely considered one of the most important scientific discoveries of the 20th century. Crick, Wilkins, and Watson each received one third of the 1962 Nobel Prize in Physiology or Medicine for their contributions to the discovery. (Franklin, whose breakthrough X-ray diffraction data was used to formulate the DNA structure, died in 1958, and thus was ineligible to be nominated for a Nobel Prize.)

    Watson and Crick proposed two strands of DNA – each in a right-hand helix – wound around the same axis. The two strands held together by H-bonding between the complimentary base pairs (A pairs with T and G pairs with C) (Figure 4.5). Note that when looking from the top view, down on a DNA base pair, that the position where the base pairs attach to the DNA backbone is not equidistant, but that attachment favors one side over the other. This creates unequal gaps or spaces in the DNA known as the major groove for the larger gap, and the minor groove for the smaller gap (Figure 4.5). Based on the DNA sequence within the region, the hydrogen-bond potential created by the nitrogen and oxygen atoms present in the nitrogenous base pairs cause unique recognition features within the major and minor grooves, allowing for specific protein recognition sites to be created.

    Figure 4.5 The Major and Minor Grooves of DNA. Top view of an (A) A-T base pair and a (B) G-C base pair showing the formation of the major and minor groove sides of the DNA. (C) Side view of the DNA double helix with the major and minor grooves indicated. The DNA backbone is shown in green, potential nitrogen hydrogen-bonding locations are indicated in blue, and oxygen hydrogen-bonding locations in red.

    Figure C modified from: dullhunk

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    Here is a dynamic model showing the major and minor grooves.

    The two sugar-phosphate backbones are shown in green and yellow. Some of the red (oxygen) and blue (nitrogen) atoms in the major and to a much less extent the minor groove are not involve in intrastrand G-C and A-T base pairing and so would available to hydrogen bond with binding proteins to which they could form complementary hydrogen bonds.

    In addition to the major and minor grooves providing variation within the double helix structure, the axis alignment of the helix along with other influencing factors such as the degree of solvation, can give rise to three forms of the double helix, the A-form (A-DNA), the B-form (B-DNA), and the Z-form (Z-DNA) (Figure 4.6). Both the A- and B-forms of the double helix are right-handed spirals, with the B-form being the predominant form found in vivo. The A-form helix arises when conditions of dehydration below 75% of normal occur and have mainly been observed in vitro during X-ray crystallography experiments when the DNA helix has become dessicated. However, the A-form of the double helix can occur in vivo when RNA adopts a double stranded conformation, or when RNA-DNA complexes form. The 2′-OH group of the ribose sugar backbone in the RNA molecule prevents the RNA-DNA hybrid from adopting the B-conformation due to steric hindrance.

    The third type of double helix formed is a left-handed helical structure known as the Z-form, or Z-DNA. Within this structural motif, the phosphates within the backbone appear to zigzag, providing the name Z-DNA (Figure 4.6). In vitro, the Z-form of DNA is adopted in short sequences that alternate pyrimidine and purines and when high salinity is present. However, the Z-form has been identified in vivo, within short regions of the DNA, showing that DNA is quite flexible and can adopt a variety of conformations. A comparison of features between A-, B- and Z-form DNA is shown in Table 4.1.

    Dimensions of B-form (the most common) of DNA

    • 0.34 nm between bp, 3.4 nm per turn, about 10 bp per turn
    • 1.9 nm (about 2.0 nm or 20 Angstroms) in diameter
    Figure 4.6 Major Conformations of the DNA Double Helix. (A) Shows from the top view, the different locations of the central axis in the different major forms of DNA, with the base pairs represented in the B-conformation. Side view of (B) A-form DNA, (C) B-form DNA, and (D) Z-form DNA.

    Image A from: Lankenau

    Images B-D from: Börner, et al (2016) Coordination Chemistry Reviews 327 DOI 10.1016/j.ccr.2016.06.002

    Table 4.1 Comparisons of B-form, A-form and Z‑DNA
      B-Form A-Form Z-Form
    helix sense Right Handed Right Handed Left Handed
    base pairs per turn 10 11 12
    vertical rise per bp 3.4 Å 2.56 Å 19 Å
    rotation per bp +36° +33° -30°
    helical diameter 19 Å 19 Å 19 Å

    The double stranded helix of DNA is not always stable. This is because the stair step links between the strands are noncovalent, reversible interactions. Depending on the DNA sequence, denaturation (melting) can be local or widespread and enables various crucial cellular processes to take place, including DNA replication, transcription, and repair.

    Both sequence specificity and interaction (whether covalent or not) with a small compound or a protein can induce tilt, roll and twist effects that rotate the base pairs in the x, y, or z axis, respectively (Figure 4.7), and can therefore change the helix’s overall organization. Furthermore, slide or flip effects can also modify the geometrical orientation of the helix (Figure 4.7). Hence the flip effects, and (to a lesser extent) the other above-defined movements modulate the double-strand stability within the helix or at its ends. Indeed, under physiological conditions, local DNA ‘breathing’ has been evidenced at both ends of the DNA helix and B- to Z-DNA structural transitions have been observed in internal DNA regions. These types of locally open DNA structures are good substrates for specific proteins which can also induce the opening of a ‘closed’ helix. The processes of DNA replication and repair will be discussed in more detail in Chapter XX and DNA transcription and transcriptional regulation in Chapters X and Y.

    Figure 4.7 Localized Structural Modification of the DNA Double Helix. (a) Base pair orientation with x, y, and z azes result in different kinds of roatation (tilt, roll or twist) or slipping of the bases (slide, flip) regarding to the helix central axis. (b) Matove B-DNA with nearly 11 base pairs within one helical turn. (c) Mono- or bis-intercalation of a small molecule (shown in blue) between adjacent base pairs resulting in an unwinding of the DNA helix (orange arrow on the top) and a lengthening of the DNA helix (ΔLength) depending on the X and y Å values that are specific for a defined DNA intercalating compound. (d) Representation of the DNA bending, base flipping, or double strand opeing induced by some DNA destabilizing alkylating agents (adducts shown in blue). Adapted from Calladine and Drew’s schematic box representation.

    Image from: Lenglet and David-Cordonnier (2010) Journal of Nucleic Acids,

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    Here are dynamic models of A , B and Z DNA

    A DNA (440D)

    B DNA (1BNA)

    ​Z DNA (4OCB)


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