Obsolete models of DNA structure

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In addition to the variety of verified DNA structures, there have been a range of proposed DNA models that have either been disproven, or lack sufficient evidence.

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Some of these structures were proposed during the 1950s before the structure of the double helix was solved, most famously by Linus Pauling. Non-helical or "side-by-side" models of DNA were proposed in the 1970s to address what appeared at the time to be problems with the topology of circular DNA chromosomes during replication (subsequently resolved via the discovery of enzymes that modify DNA topology). [1] These were also rejected due to accumulating experimental evidence from X-ray crystallography, solution NMR, and atomic force microscopy (of both DNA alone, and bound to DNA-binding proteins). Although localised or transient non-duplex helical structures exist, [2] non-helical models are not currently accepted by the mainstream scientific community. [3] Finally, there exists a persistent set of contemporary fringe theories proposing a range of unsupported models.

Early speculative triple-helix structure (1953) Pauling DNA triplex.png
Early speculative triple-helix structure (1953)

Prior to Watson–Crick structure

The DNA double helix was discovered in 1953 [4] (with further details in 1954 [5] ) based on X-ray diffraction images of DNA (most notably photo 51, taken by Raymond Gosling and Rosalind Franklin [6] ) as well as base-pairing chemical and biochemical information. [7] [8] Prior to this, X-ray data being gathered in the 1950s indicated that DNA formed some sort of helix, but it had not yet been discovered what the exact structure of that helix was. There were therefore several proposed structures that were later overturned by the data supporting a DNA duplex. The most famous of these early models was by Linus Pauling and Robert Corey in 1953 in which they proposed a triple helix with the phosphate backbone on the inside, and the nucleotide bases pointing outwards. [9] [10] A broadly similar, but detailed structure was also proposed by Bruce Fraser that same year. [11] However, Watson and Crick soon identified several problems with these models:

The initial double helix model discovered, now termed B-form DNA is by far the most common conformation in cells. [12] Two additional rarer helical conformations that also naturally occur were identified in the 1970s: A-form DNA, and Z-form DNA. [13]

Non-helical structure proposals

Before the discovery of topoisomerases

Linear tetraplex model proposal (1969) [14]

Even once the DNA duplex structure was solved, it was initially an open question whether additional DNA structures were needed to explain its overall topology. there were initially questions about how it might affect DNA replication. In 1963, autoradiographs of the E. coli chromosome demonstrated that it was a single circular molecule that is replicated at a pair of replication forks at which both new DNA strands are being synthesized. [15] The two daughter chromosomes after replication would therefore be topologically linked. The separation of the two linked daughter DNA strands during replication either required DNA to have a net-zero helical twist, or for the strands to be cut, crossed, and rejoined. It was this apparent contradictions that early non-helical models attempted to address until the discovery of topoisomerases in 1970 resolved the problem. [16] [17]

In the 1960s and 1970s, a number of structures were hypothesised that would give a net-zero helical twist over the length of the DNA, either by being fully straight throughout or by alternating right-handed and left-handed helical twists. [18] [19] For example, in 1969, a linear tetramer structure was hypothesised, [14] and in 1976, a structure with alternating sections of right-handed and left-handed helix was independently proposed by two different groups. [20] [21] The alternating twists model was initially presented with the helicity changing every half turn, but later long stretches of each helical direction were later proposed. [22] However, these models suffered from a lack of experimental support. [23] Under torsional stress, a Z-DNA structure can form with opposite twist to B-form DNA, but this is rare within the cellular environment. [24] The discovery of topoisomerases and gyrases, enzymes that can change the linking number of circular nucleic acids and thus "unwind" and "rewind" the replicating bacterial chromosome, solved the topological objections to the B-form DNA helical structure. [25] Indeed, in the absence of these topology-altering enzymes, small circular viral and plasmid DNA are inseparable supporting structure whose strands are topologically locked together. [26]

Non-helical DNA proposals have therefore dropped from mainstream science. [3] [16]

Side-By-Side model structure proposal (1976) [18]

Confirmation of helical structure

Initially, there had been questions of whether the solved DNA structures were artefacts of the X-ray crystallography techniques used. However, the structure of DNA was subsequently confirmed in solution via gel electrophoretic methods [27] and later via solution NMR [28] and AFM [29] indicating that the crystallography process did not distort it. The structure of DNA in complex with nucleosomes, helicases, and numerous other DNA binding proteins also supported its biological relevance in vivo. [30]

Related Research Articles

<span class="mw-page-title-main">Alpha helix</span> Type of secondary structure of proteins

An alpha helix is a sequence of amino acids in a protein that are twisted into a coil.

<span class="mw-page-title-main">DNA</span> Molecule that carries genetic information

Deoxyribonucleic acid is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. 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.

<span class="mw-page-title-main">Francis Crick</span> English physicist, molecular biologist; co-discoverer of the structure of DNA

Francis Harry Compton Crick was an English molecular biologist, biophysicist, and neuroscientist. He, James Watson, Rosalind Franklin, and Maurice Wilkins played crucial roles in deciphering the helical structure of the DNA molecule.

<span class="mw-page-title-main">Protein secondary structure</span> General three-dimensional form of local segments of proteins

Protein secondary structure is the local spatial conformation of the polypeptide backbone excluding the side chains. The two most common secondary structural elements are alpha helices and beta sheets, though beta turns and omega loops occur as well. Secondary structure elements typically spontaneously form as an intermediate before the protein folds into its three dimensional tertiary structure.

Semiconservative replication describes the mechanism of DNA replication in all known cells. DNA replication occurs on multiple origins of replication along the DNA template strands. As the DNA double helix is unwound by helicase, replication occurs separately on each template strand in antiparallel directions. This process is known as semi-conservative replication because two copies of the original DNA molecule are produced, each copy conserving (replicating) the information from one half of the original DNA molecule. Each copy contains one original strand and one newly synthesized strand. The structure of DNA suggested that each strand of the double helix would serve as a template for synthesis of a new strand. It was not known how newly synthesized strands combined with template strands to form two double helical DNA molecules.

DNA topoisomerases are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. A second topological challenge results from the linking or tangling of DNA during replication. Left unresolved, links between replicated DNA will impede cell division. The DNA topoisomerases prevent and correct these types of topological problems. They do this by binding to DNA and cutting the sugar-phosphate backbone of either one or both of the DNA strands. This transient break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed. Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology.

<span class="mw-page-title-main">Z-DNA</span> One of many possible double helical structures of DNA

Z-DNA is one of the many possible double helical structures of DNA. It is a left-handed double helical structure in which the helix winds to the left in a zigzag pattern, instead of to the right, like the more common B-DNA form. Z-DNA is thought to be one of three biologically active double-helical structures along with A-DNA and B-DNA.

<span class="mw-page-title-main">Triple-stranded DNA</span> DNA structure

Triple-stranded DNA is a DNA structure in which three oligonucleotides wind around each other and form a triple helix. In triple-stranded DNA, the third strand binds to a B-form DNA double helix by forming Hoogsteen base pairs or reversed Hoogsteen hydrogen bonds.

<span class="mw-page-title-main">Nucleic acid double helix</span> Structure formed by double-stranded molecules

In molecular biology, the term double helix refers to the structure formed by double-stranded molecules of nucleic acids such as DNA. The double helical structure of a nucleic acid complex arises as a consequence of its secondary structure, and is a fundamental component in determining its tertiary structure. The structure was discovered by Maurice Wilkins, Rosalind Franklin, her student Raymond Gosling, James Watson, and Francis Crick, while the term "double helix" entered popular culture with the 1968 publication of Watson's The Double Helix: A Personal Account of the Discovery of the Structure of DNA.

<span class="mw-page-title-main">Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid</span> 1953 scientific paper on DNA

"Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid" was the first article published to describe the discovery of the double helix structure of DNA, using X-ray diffraction and the mathematics of a helix transform. It was published by Francis Crick and James D. Watson in the scientific journal Nature on pages 737–738 of its 171st volume.

The history of molecular biology begins in the 1930s with the convergence of various, previously distinct biological and physical disciplines: biochemistry, genetics, microbiology, virology and physics. With the hope of understanding life at its most fundamental level, numerous physicists and chemists also took an interest in what would become molecular biology.

<span class="mw-page-title-main">DNA supercoil</span> Amount of twist in a particular DNA strand

DNA supercoiling refers to the amount of twist in a particular DNA strand, which determines the amount of strain on it. A given strand may be "positively supercoiled" or "negatively supercoiled". The amount of a strand's supercoiling affects a number of biological processes, such as compacting DNA and regulating access to the genetic code. Certain enzymes, such as topoisomerases, change the amount of DNA supercoiling to facilitate functions such as DNA replication and transcription. The amount of supercoiling in a given strand is described by a mathematical formula that compares it to a reference state known as "relaxed B-form" DNA.

3<sub>10</sub> helix Type of secondary structure

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<span class="mw-page-title-main">Type II topoisomerase</span> Class of enzymes

Type II topoisomerases are topoisomerases that cut both strands of the DNA helix simultaneously in order to manage DNA tangles and supercoils. They use the hydrolysis of ATP, unlike Type I topoisomerase. In this process, these enzymes change the linking number of circular DNA by ±2. Topoisomerases are ubiquitous enzymes, found in all living organisms.

<span class="mw-page-title-main">Molecular models of DNA</span>

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<span class="mw-page-title-main">Nucleic acid tertiary structure</span> Three-dimensional shape of a nucleic acid polymer

Nucleic acid tertiary structure is the three-dimensional shape of a nucleic acid polymer. RNA and DNA molecules are capable of diverse functions ranging from molecular recognition to catalysis. Such functions require a precise three-dimensional structure. While such structures are diverse and seemingly complex, they are composed of recurring, easily recognizable tertiary structural motifs that serve as molecular building blocks. Some of the most common motifs for RNA and DNA tertiary structure are described below, but this information is based on a limited number of solved structures. Many more tertiary structural motifs will be revealed as new RNA and DNA molecules are structurally characterized.

<span class="mw-page-title-main">Nucleic acid structure</span> Biomolecular structure of nucleic acids such as DNA and RNA

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<span class="mw-page-title-main">Nucleic acid secondary structure</span>

Nucleic acid secondary structure is the basepairing interactions within a single nucleic acid polymer or between two polymers. It can be represented as a list of bases which are paired in a nucleic acid molecule. The secondary structures of biological DNAs and RNAs tend to be different: biological DNA mostly exists as fully base paired double helices, while biological RNA is single stranded and often forms complex and intricate base-pairing interactions due to its increased ability to form hydrogen bonds stemming from the extra hydroxyl group in the ribose sugar.

Nucleic acid NMR is the use of nuclear magnetic resonance spectroscopy to obtain information about the structure and dynamics of nucleic acid molecules, such as DNA or RNA. It is useful for molecules of up to 100 nucleotides, and as of 2003, nearly half of all known RNA structures had been determined by NMR spectroscopy.

Viswanathan Sasisekharan is an Indian biophysicist known for his work on the structure and conformation of biopolymers. He introduced the use of torsion angles to describe polypeptide and protein conformation, a central principle of the plot. Additionally, he was the first to introduce alternative models of DNA structure that provided insights beyond the standard double helix model. For his contributions to the biological sciences, he was awarded the Shanti Swarup Bhatnagar Prize for Science and Technology, one of India’s highest science awards, in 1978.

References

  1. ↑ Stokes, T. D. (1982). "The double helix and the warped zipper—an exemplary tale". Social Studies of Science . 12 (2): 207–240. doi:10.1177/030631282012002002. PMID   11620855. S2CID   29369576.
  2. ↑ Sinden, Richard R. (1994). "Miscellaneous Alternative Conformations of DNA". DNA Structure and Function. Elsevier. pp. 259–286. doi:10.1016/b978-0-08-057173-7.50012-2. ISBN   9780080571737.
  3. 1 2 Gautham, N. (2004). "Response to "Variety in DNA secondary structure"" (PDF). Current Science . 86 (10): 1352–1353. However, the discovery of topoisomerases took "the sting" out of the topological objection to the plectonaemic double helix. The more recent solution of the single crystal X-ray structure of the nucleosome core particle showed nearly 150 base pairs of the DNA (i.e. about 15 complete turns), with a structure that is in all essential respects the same as the Watson–Crick model. This dealt a death blow to the idea that other forms of DNA, particularly double helical DNA, exist as anything other than local or transient structures.
  4. ↑ Watson, J. D.; Crick, F. (1953). "A structure for deoxyribose nucleic acid" (PDF). Nature . 171 (4356): 737–8. Bibcode:1953Natur.171..737W. doi:10.1038/171737a0. PMID   13054692. S2CID   4253007.
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  6. ↑ "The story behind Photograph 51 | Feature from King's College London". www.kcl.ac.uk. Retrieved 2023-08-29.
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  9. ↑ Pauling L, Corey RB (February 1953). "A Proposed Structure For The Nucleic Acids". Proceedings of the National Academy of Sciences of the United States of America. 39 (2): 84–97. Bibcode:1953PNAS...39...84P. doi: 10.1073/pnas.39.2.84 . PMC   1063734 . PMID   16578429.
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  12. ↑ Richmond TJ, Davey CA (2003). "The structure of DNA in the nucleosome core". Nature. 423 (6936): 145–50. Bibcode:2003Natur.423..145R. doi:10.1038/nature01595. PMID   12736678. S2CID   205209705.
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  14. 1 2 Wu, Tai Te (1969). "Secondary Structures of DNA". Proceedings of the National Academy of Sciences . 63 (2): 400–405. doi: 10.1073/pnas.63.2.400 . ISSN   0027-8424. PMC   223578 . PMID   5257129.
  15. ↑ Cairns, J. (1963). "The bacterial chromosome and its manner of replication as seen by autoradiography". J. Mol. Biol. 6 (3): 208–13. doi:10.1016/s0022-2836(63)80070-4. PMID   14017761.
  16. 1 2 Biegeleisen K (2002). "Topologically non-linked circular duplex DNA". Bull. Math. Biol. 64 (3): 589–609. CiteSeerX   10.1.1.573.5418 . doi:10.1006/bulm.2002.0288. PMID   12094410. S2CID   13269612.
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  18. 1 2 Rodley GA, Scobie RS, Bates RH, Lewitt RM (1976). "A possible conformation for double-stranded polynucleotides". Proc. Natl. Acad. Sci. U.S.A. 73 (9): 2959–63. Bibcode:1976PNAS...73.2959R. doi: 10.1073/pnas.73.9.2959 . PMC   430891 . PMID   1067594.
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  20. ↑ Sasisekharan, V.; Pattabiraman, N. (1976). "Double stranded polynucleotides: two typical alternative conformations for nucleic acids". Current Science . 45: 779–783.
  21. ↑ Sasisekharan, V.; Pattabiraman, N.; Gupta, G. (1978). "Some implications of an alternative structure for DNA". Proc. Natl. Acad. Sci. U.S.A. 75 (9): 4092–6. Bibcode:1978PNAS...75.4092S. doi: 10.1073/pnas.75.9.4092 . PMC   336057 . PMID   279899.
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  24. ↑ Rich, Alexander; Zhang, Shuguang (2003). "Z-DNA: the long road to biological function". Nature Reviews Genetics. 4 (7): 566–572. doi:10.1038/nrg1115. ISSN   1471-0064. PMID   12838348. S2CID   835548.
  25. ↑ Keszthelyi, Andrea; Minchell, Nicola; Baxter, Jonathan (2016). "The Causes and Consequences of Topological Stress during DNA Replication". Genes . 7 (12): 134. doi: 10.3390/genes7120134 . ISSN   2073-4425. PMC   5192510 . PMID   28009828.
  26. ↑ Vinograd J, Lebowitz J, Radloff R, Watson R, Laipis P (1965). "The twisted circular form of polyoma viral DNA". Proc. Natl. Acad. Sci. U.S.A. 53 (5): 1104–11. Bibcode:1965PNAS...53.1104V. doi: 10.1073/pnas.53.5.1104 . PMC   301380 . PMID   4287964.
  27. ↑ Wang, J. C. (1979). "Helical repeat of DNA in solution". Proceedings of the National Academy of Sciences . 76 (1): 200–203. Bibcode:1979PNAS...76..200W. doi: 10.1073/pnas.76.1.200 . ISSN   0027-8424. PMC   382905 . PMID   284332.
  28. ↑ Ghosh, Anirban; Kar, Rajiv Kumar; Jana, Jagannath; Saha, Abhijit; Jana, Batakrishna; Krishnamoorthy, Janarthanan; Kumar, Dinesh; Ghosh, Surajit; Chatterjee, Subhrangsu (2014). "Indolicidin Targets Duplex DNA: Structural and Mechanistic Insight through a Combination of Spectroscopy and Microscopy". ChemMedChem . 9 (9): 2052–2058. doi:10.1002/cmdc.201402215. hdl: 2027.42/108345 . ISSN   1860-7179. PMID   25044630. S2CID   33138700.
  29. ↑ Pyne, Alice; Thompson, Ruth; Leung, Carl; Roy, Debdulal; Hoogenboom, Bart W. (2014). "Single-Molecule Reconstruction of Oligonucleotide Secondary Structure by Atomic Force Microscopy" (PDF). Small. 10 (16): 3257–3261. doi:10.1002/smll.201400265. ISSN   1613-6829. PMID   24740866. S2CID   5050707.
  30. ↑ Morgunova, E.; Taipale, J. (2017). "Structural perspective of cooperative transcription factor binding". Current Opinion in Structural Biology . Protein–nucleic acid interactions • Catalysis and regulation. 47: 1–8. doi: 10.1016/j.sbi.2017.03.006 . ISSN   0959-440X. PMID   28349863.
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