Molecular models of DNA

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DNA in water.jpg
DNA animation.gif
While this purified DNA precipitated in a flask of water (left) appears to be a formless mass to the naked eye, at the nanoscale, nucleic acids possess intricate structure (right).

Molecular models of DNA structures are representations of the molecular geometry and topology of deoxyribonucleic acid (DNA) molecules using one of several means, with the aim of simplifying and presenting the essential, physical and chemical, properties of DNA molecular structures either in vivo or in vitro. These representations include closely packed spheres (CPK models) made of plastic, metal wires for skeletal models, graphic computations and animations by computers, artistic rendering. Computer molecular models also allow animations and molecular dynamics simulations that are very important for understanding how DNA functions in vivo.

Contents

The more advanced, computer-based molecular models of DNA involve molecular dynamics simulations and quantum mechanics computations of vibro-rotations, delocalized molecular orbitals (MOs), electric dipole moments, hydrogen-bonding, and so on. DNA molecular dynamics modeling involves simulating deoxyribonucleic acid (DNA) molecular geometry and topology changes with time as a result of both intra- and inter- molecular interactions of DNA. Whereas molecular models of DNA molecules such as closely packed spheres (CPK models) made of plastic or metal wires for skeletal models are useful representations of static DNA structures, their usefulness is very limited for representing complex DNA dynamics. Computer molecular modeling allows both animations and molecular dynamics simulations that are very important to understand how DNA functions in vivo .

History

The A-DNA double helix molecular model of Crick and Watson (consistent with X-ray data) for which they, with M.H.F. Wilkins, received a Nobel Prize. DNA Model Crick-Watson.jpg
The A-DNA double helix molecular model of Crick and Watson (consistent with X-ray data) for which they, with M.H.F. Wilkins, received a Nobel Prize.

From the very early stages of structural studies of DNA by X-ray diffraction and biochemical means, molecular models such as the Watson-Crick nucleic acid double helix model were successfully employed to solve the 'puzzle' of DNA structure, and also find how the latter relates to its key functions in living cells. The first high quality X-ray diffraction patterns of A-DNA were reported by Rosalind Franklin and Raymond Gosling in 1953. [1] Rosalind Franklin made the critical observation that DNA exists in two distinct forms, A and B, and produced the sharpest pictures of both through X-ray diffraction technique. [2] The first calculations of the Fourier transform of an atomic helix were reported one year earlier by Cochran, Crick and Vand, [3] and were followed in 1953 by the computation of the Fourier transform of a coiled-coil by Crick. [4]

Structural information is generated from X-ray diffraction studies of oriented DNA fibers with the help of molecular models of DNA that are combined with crystallographic and mathematical analysis of the X-ray patterns.

The first reports of a double helix molecular model of B-DNA structure were made by James Watson and Francis Crick in 1953. [5] [6] That same year, Maurice F. Wilkins, A. Stokes and H.R. Wilson, reported the first X-ray patterns of in vivo B-DNA in partially oriented salmon sperm heads. [7]

The development of the first correct double helix molecular model of DNA by Crick and Watson may not have been possible without the biochemical evidence for the nucleotide base-pairing ([A---T]; [C---G]), or Chargaff's rules. [8] [9] [10] [11] [12] [13] Although such initial studies of DNA structures with the help of molecular models were essentially static, their consequences for explaining the in vivo functions of DNA were significant in the areas of protein biosynthesis and the quasi-universality of the genetic code. Epigenetic transformation studies of DNA in vivo were however much slower to develop despite their importance for embryology, morphogenesis and cancer research. Such chemical dynamics and biochemical reactions of DNA are much more complex than the molecular dynamics of DNA physical interactions with water, ions and proteins/enzymes in living cells.

Importance

An old standing dynamic problem is how DNA "self-replication" takes place in living cells that should involve transient uncoiling of supercoiled DNA fibers. Although DNA consists of relatively rigid, very large elongated biopolymer molecules called fibers or chains (that are made of repeating nucleotide units of four basic types, attached to deoxyribose and phosphate groups), its molecular structure in vivo undergoes dynamic configuration changes that involve dynamically attached water molecules and ions. Supercoiling, packing with histones in chromosome structures, and other such supramolecular aspects also involve in vivo DNA topology which is even more complex than DNA molecular geometry, thus turning molecular modeling of DNA into an especially challenging problem for both molecular biologists and biotechnologists. Like other large molecules and biopolymers, DNA often exists in multiple stable geometries (that is, it exhibits conformational isomerism) and configurational, quantum states which are close to each other in energy on the potential energy surface of the DNA molecule.

Such varying molecular geometries can also be computed, at least in principle, by employing ab initio quantum chemistry methods that can attain high accuracy for small molecules, although claims that acceptable accuracy can be also achieved for polynuclelotides, and DNA conformations, were recently made on the basis of vibrational circular dichroism (VCD) spectral data. Such quantum geometries define an important class of ab initio molecular models of DNA which exploration has barely started, especially related to results obtained by VCD in solutions. More detailed comparisons with such ab initio quantum computations are in principle obtainable through 2D-FT NMR spectroscopy and relaxation studies of polynucleotide solutions or specifically labeled DNA, as for example with deuterium labels.

In an interesting twist of roles, the DNA molecule was proposed to be used for quantum computing via DNA. Both DNA nanostructures and DNA computing biochips have been built.

Fundamental concepts

DNA chemical structure.svg
DNA-fragment-3D-vdW.png
At left, the chemical structure of DNA showing the base-pairing. This depiction of a DNA duplex lacks information about the molecule's three-dimensional structure, at right.

The chemical structure of DNA is insufficient to understand the complexity of the 3D structures of DNA. In contrast, animated molecular models allow one to visually explore the three-dimensional (3D) structure of DNA. The DNA model shown (far right) is a space-filling, or CPK, model of the DNA double helix. Animated molecular models, such as the wire, or skeletal, type shown at the top of this article, allow one to visually explore the three-dimensional (3D) structure of DNA. Another type of DNA model is the space-filling, or CPK, model.

The hydrogen bonding dynamics and proton exchange is very different by many orders of magnitude between the two systems of fully hydrated DNA and water molecules in ice. Thus, the DNA dynamics is complex, involving nanosecond and several tens of picosecond time scales, whereas that of liquid ice is on the picosecond time scale, and that of proton exchange in ice is on the millisecond time scale. The proton exchange rates in DNA and attached proteins may vary from picosecond to nanosecond, minutes or years, depending on the exact locations of the exchanged protons in the large biopolymers.

A simple harmonic oscillator 'vibration' is only an oversimplified dynamic representation of the longitudinal vibrations of the DNA intertwined helices which were found to be anharmonic rather than harmonic as often assumed in quantum dynamic simulations of DNA.

DNA structure

The structure of DNA shows a variety of forms, both double-stranded and single-stranded. The mechanical properties of DNA, which are directly related to its structure, are a significant problem for cells. Every process which binds or reads DNA is able to use or modify the mechanical properties of DNA for purposes of recognition, packaging and modification. The extreme length (a chromosome may contain a 10 cm long DNA strand), relative rigidity and helical structure of DNA has led to the evolution of histones and of enzymes such as topoisomerases and helicases to manage a cell's DNA. The properties of DNA are closely related to its molecular structure and sequence, particularly the weakness of the hydrogen bonds and electronic interactions that hold strands of DNA together compared to the strength of the bonds within each strand.

Experimental methods which can directly measure the mechanical properties of DNA are relatively new, and high-resolution visualization in solution is often difficult. Nevertheless, scientists have uncovered large amount of data on the mechanical properties of this polymer, and the implications of DNA's mechanical properties on cellular processes is a topic of active current research.

The DNA found in many cells can be macroscopic in length: a few centimetres long for each human chromosome. Consequently, cells must compact or package DNA to carry it within them. In eukaryotes this is carried by spool-like proteins named histones, around which DNA winds. It is the further compaction of this DNA-protein complex which produces the well known mitotic eukaryotic chromosomes.

In the late 1970s, alternate non-helical models of DNA structure were briefly considered as a potential solution to problems in DNA replication in plasmids and chromatin. However, the models were set aside in favor of the double-helical model due to subsequent experimental advances such as X-ray crystallography of DNA duplexes, and later the nucleosome core particle, and the discovery of topoisomerases. Such non-double-helical models are not currently accepted by the mainstream scientific community. [14] [15]

DNA structure determination using molecular modeling and DNA X-ray patterns

X ray diffraction.png
ABDNAxrgpj.jpg
Left, the major steps involved in DNA structure determination by X-ray crystallography showing the important role played by molecular models of DNA structure in this iterative process. Right, an image of actual A- and B- DNA X-ray patterns obtained from oriented and hydrated DNA fibers (courtesy of Dr. Herbert R. Wilson, FRS- see refs. list).

After DNA has been separated and purified by standard biochemical methods, one has a sample in a jar much like in the figure at the top of this article. Below are the main steps involved in generating structural information from X-ray diffraction studies of oriented DNA fibers that are drawn from the hydrated DNA sample with the help of molecular models of DNA that are combined with crystallographic and mathematical analysis of the X-ray patterns.

Paracrystalline lattice models of B-DNA structures

Silica glass is another example of a material which is organized into a paracrystalline lattice. Silica.svg
Silica glass is another example of a material which is organized into a paracrystalline lattice.

A paracrystalline lattice, or paracrystal, is a molecular or atomic lattice with significant amounts (e.g., larger than a few percent) of partial disordering of molecular arrangements. Limiting cases of the paracrystal model are nanostructures, such as glasses, liquids, etc., that may possess only local ordering and no global order. A simple example of a paracrystalline lattice is shown in the following figure for a silica glass:

Liquid crystals also have paracrystalline rather than crystalline structures.

Highly hydrated B-DNA occurs naturally in living cells in such a paracrystalline state, which is a dynamic one despite the relatively rigid DNA double helix stabilized by parallel hydrogen bonds between the nucleotide base-pairs in the two complementary, helical DNA chains (see figures). For simplicity most DNA molecular models omit both water and ions dynamically bound to B-DNA, and are thus less useful for understanding the dynamic behaviors of B-DNA in vivo. The physical and mathematical analysis of X-ray [16] [17] and spectroscopic data for paracrystalline B-DNA is thus far more complex than that of crystalline, A-DNA X-ray diffraction patterns. The paracrystal model is also important for DNA technological applications such as DNA nanotechnology. Novel methods that combine X-ray diffraction of DNA with X-ray microscopy in hydrated living cells are now also being developed. [18]

Genomic and biotechnology applications of DNA molecular modeling

Molecular models are useful in the design of structures for DNA nanotechnology. Here, individual DNA tiles (model at left) self-assemble into a highly ordered DNA 2D-nanogrid (AFM image at right). DNA nanostructures.png
Molecular models are useful in the design of structures for DNA nanotechnology. Here, individual DNA tiles (model at left) self-assemble into a highly ordered DNA 2D-nanogrid (AFM image at right).

There are various uses of DNA molecular modeling in Genomics and Biotechnology research applications, from DNA repair to PCR and DNA nanostructures. Two-dimensional DNA junction arrays have been visualized by Atomic force microscopy. [19]

DNA molecular modeling has various uses in genomics and biotechnology, with research applications ranging from DNA repair to PCR and DNA nanostructures. These include computer molecular models of molecules as varied as RNA polymerase, an E. coli, bacterial DNA primase template suggesting very complex dynamics at the interfaces between the enzymes and the DNA template, and molecular models of the mutagenic, chemical interaction of potent carcinogen molecules with DNA. These are all represented in the gallery below.

Technological application include a DNA biochip and DNA nanostructures designed for DNA computing and other dynamic applications of DNA nanotechnology. [20] [21] [22] [23] [24] [25] The image at right is of self-assembled DNA nanostructures. The DNA "tile" structure in this image consists of four branched junctions oriented at 90° angles. Each tile consists of nine DNA oligonucleotides as shown; such tiles serve as the primary "building block" for the assembly of the DNA nanogrids shown in the AFM micrograph.

Quadruplex DNA may be involved in certain cancers. [26] [27] Images of quadruplex DNA are in the gallery below.

See also

Related Research Articles

<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">Structural biology</span> Study of molecular structures in biology

Structural biology, as defined by the Journal of Structural Biology, deals with structural analysis of living material at every level of organization.

<span class="mw-page-title-main">Maurice Wilkins</span> New Zealand-born British biophysicist

Maurice Hugh Frederick Wilkins was a New Zealand-born British biophysicist and Nobel laureate whose research spanned multiple areas of physics and biophysics, contributing to the scientific understanding of phosphorescence, isotope separation, optical microscopy, and X-ray diffraction. He is known for his work at King's College London on the structure of DNA.

<span class="mw-page-title-main">Structural bioinformatics</span> Bioinformatics subfield

Structural bioinformatics is the branch of bioinformatics that is related to the analysis and prediction of the three-dimensional structure of biological macromolecules such as proteins, RNA, and DNA. It deals with generalizations about macromolecular 3D structures such as comparisons of overall folds and local motifs, principles of molecular folding, evolution, binding interactions, and structure/function relationships, working both from experimentally solved structures and from computational models. The term structural has the same meaning as in structural biology, and structural bioinformatics can be seen as a part of computational structural biology. The main objective of structural bioinformatics is the creation of new methods of analysing and manipulating biological macromolecular data in order to solve problems in biology and generate new knowledge.

<span class="mw-page-title-main">Hoogsteen base pair</span> Nucleic acid pairing variations

A Hoogsteen base pair is a variation of base-pairing in nucleic acids such as the A•T pair. In this manner, two nucleobases, one on each strand, can be held together by hydrogen bonds in the major groove. A Hoogsteen base pair applies the N7 position of the purine base and C4 amino group, which bind the Watson–Crick (N3–C4) face of the pyrimidine base.

<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">Raymond Gosling</span> British physicist

Raymond George Gosling was a British scientist. While a PhD student at King's College, London he worked under the supervision of Maurice Wilkins and Rosalind Franklin. The crystallographic experiments of Franklin and Gosling, together with others by Wilkins, produced data that helped James Watson and Francis Crick to infer 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.

Alexander Rawson Stokes was a British physicist at Royal Holloway College, London and later at King's College London. He was most recognised as a co-author of the second of the three papers published sequentially in Nature on 25 April 1953 describing the correct molecular structure of DNA. The first was authored by Francis Crick and James Watson, and the third by Rosalind Franklin and Raymond Gosling.

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">Biomolecular structure</span> 3D conformation of a biological sequence, like DNA, RNA, proteins

Biomolecular structure is the intricate folded, three-dimensional shape that is formed by a molecule of protein, DNA, or RNA, and that is important to its function. The structure of these molecules may be considered at any of several length scales ranging from the level of individual atoms to the relationships among entire protein subunits. This useful distinction among scales is often expressed as a decomposition of molecular structure into four levels: primary, secondary, tertiary, and quaternary. The scaffold for this multiscale organization of the molecule arises at the secondary level, where the fundamental structural elements are the molecule's various hydrogen bonds. This leads to several recognizable domains of protein structure and nucleic acid structure, including such secondary-structure features as alpha helixes and beta sheets for proteins, and hairpin loops, bulges, and internal loops for nucleic acids. The terms primary, secondary, tertiary, and quaternary structure were introduced by Kaj Ulrik Linderstrøm-Lang in his 1951 Lane Medical Lectures at Stanford University.

Experimental approaches of determining the structure of nucleic acids, such as RNA and DNA, can be largely classified into biophysical and biochemical methods. Biophysical methods use the fundamental physical properties of molecules for structure determination, including X-ray crystallography, NMR and cryo-EM. Biochemical methods exploit the chemical properties of nucleic acids using specific reagents and conditions to assay the structure of nucleic acids. Such methods may involve chemical probing with specific reagents, or rely on native or analogue chemistry. Different experimental approaches have unique merits and are suitable for different experimental purposes.

<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">DNA nanotechnology</span> The design and manufacture of artificial nucleic acid structures for technological uses

DNA nanotechnology is the design and manufacture of artificial nucleic acid structures for technological uses. In this field, nucleic acids are used as non-biological engineering materials for nanotechnology rather than as the carriers of genetic information in living cells. Researchers in the field have created static structures such as two- and three-dimensional crystal lattices, nanotubes, polyhedra, and arbitrary shapes, and functional devices such as molecular machines and DNA computers. The field is beginning to be used as a tool to solve basic science problems in structural biology and biophysics, including applications in X-ray crystallography and nuclear magnetic resonance spectroscopy of proteins to determine structures. Potential applications in molecular scale electronics and nanomedicine are also being investigated.

<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.

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

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.

<span class="mw-page-title-main">DNA base flipping</span> Biochemical process

DNA base flipping, or nucleotide flipping, is a mechanism in which a single nucleotide base, or nucleobase, is rotated outside the nucleic acid double helix. This occurs when a nucleic acid-processing enzyme needs access to the base to perform work on it, such as its excision for replacement with another base during DNA repair. It was first observed in 1994 using X-ray crystallography in a methyltransferase enzyme catalyzing methylation of a cytosine base in DNA. Since then, it has been shown to be used by different enzymes in many biological processes such as DNA methylation, various DNA repair mechanisms, and DNA replication. It can also occur in RNA double helices or in the DNA:RNA intermediates formed during RNA transcription.

Structural chemistry is a part of chemistry and deals with spatial structures of molecules and solids. For structure elucidation a range of different methods is used. One has to distinguish between methods that elucidate solely the connectivity between atoms (constitution) and such that provide precise three dimensional information such as atom coordinates, bond lengths and angles and torsional angles.

References

  1. ↑ Franklin, R.E., Gosling, R.G. (6 March 1953). "The Structure of Sodium Thymonucleate Fibres I. The Influence of Water Content". Acta Crystallogr. 6 (8): 673. Bibcode:1953AcCry...6..673F. doi: 10.1107/S0365110X53001939 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
    Franklin, R.E., Gosling, R.G. (6 March 1953). "The Structure of Sodium Thymonucleate Fibres II. The Cylindrically Symmetrical Patterson Function". Acta Crystallogr. 6 (8): 678. Bibcode:1953AcCry...6..678F. doi: 10.1107/S0365110X53001940 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Hammer, DEAN H.; Maddox, Brenda (2002). "The Twisted Road to the Double Helix". Scientific American. 287 (6): 127–128. Bibcode:2002SciAm.287f.127H. doi:10.1038/scientificamerican1202-127. JSTOR   26060090.
  3. ↑ Cochran, W., Crick, F.H.C., Vand V. (1952). "The Structure of Synthetic Polypeptides. 1. The Transform of Atoms on a Helix". Acta Crystallogr. 5 (5): 581–6. Bibcode:1952AcCry...5..581C. doi: 10.1107/S0365110X52001635 .{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ↑ Crick, F.H.C. (1953a). "The Fourier Transform of a Coiled-Coil". Acta Crystallogr. 6 (8–9): 685–9. Bibcode:1953AcCry...6..685C. doi: 10.1107/S0365110X53001952 .
  5. ↑ Watson, James D., Crick, Francis H.C. (25 April 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.{{cite journal}}: CS1 maint: multiple names: authors list (link), .
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  26. ↑ "Department of Physics, Cavendish Laboratory - Molecular Biophysics". Archived from the original on 23 May 2009. Retrieved 17 May 2009.
  27. ↑ "Kryptowährungen und Physik – Planetphysics". Archived from the original on 31 March 2009. Retrieved 17 May 2009.

Further reading

Databases for DNA molecular models and sequences

X-ray diffraction
Neutron scattering
X-ray microscopy
Electron microscopy
NMR databases
Genomic and structural databases
Atomic force microscopy

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