Nucleic Acids
“DNA was the first three-dimensional Xerox machine.” ~ English economist and sociologist Kenneth Boulding
Swiss physician and biologist Friedrich Miescher isolated various phosphate-rich chemicals from the nuclei of white blood cells in 1869. He called them nuclein because they seemed to come from the nuclei of cells.
A few years later, nuclein were found to be slightly acidic, so they became known as nucleic acids. No one knew what the substance was or was for. As well as having different functions, nucleic acids are chemically different than amino acids.
Nucleic acids are biopolymers; specifically, RNA (ribonucleic acid) and DNA (deoxyribonucleic acid), both polynucleotides. A biopolymer is a polymer produced by a cell. A polynucleotide is a biopolymer of 13 or more nucleotide monomers chained together by covalent bonds.
Deciphering DNA
It now seems certain that the amino acid sequence of any protein is determined by the sequence of bases in some region of a particular nucleic acid molecule. ~ Francis Crick
Continuous research of nucleic acids followed the typical path of scientific inquiry: mistaken hunches and endless experimentation to suss structure and function, until insight puts the pieces together and fills the evidentiary gaps.
By 1929, Russian American biochemist Phoebus Levene had identified the components of DNA & RNA and coined the term nucleotide, though his ideas about the structure of DNA were wrong.
English chemist and X-ray crystallographer Rosalind Franklin managed the first snapshots of DNA in 1951 via X-ray diffraction imagery. With her wealth of accumulated image data and analysis, Franklin significantly furthered understanding of DNA’s intricate structure.
Franklin correctly surmised that DNA was a double-stranded helix, with each helix having 4 nucleobases (nucleic acid bases) attached to a phosphate-sugar backbone. The DNA bases are adenine (A), cytosine (C), guanine (G), and thymine (T).
These results she shared at a seminar attended by American biologist James Watson and English biologist Francis Crick, who were graduate students at Cambridge University. Franklin worked at nearby King’s College.
Watson & Crick completed figuring out the 3-dimensional structure of DNA in 1953, after building innumerable physical models. Their first models were quite off: a triple helix, not double; and the bases on the outside, not inside where they belonged.
Watson & Crick got an advance publication copy of DNA work by American chemist Linus Pauling from Peter Pauling, Linus’ son, who worked in the same lab as Watson & Crick. Pauling’s paper wrongly had the triple helix, wrongly put the bases on the outside, and wrongly characterized the phosphate groups by not ionizing them. Pauling, then a world-renown chemist, made careless schoolboy blunders in his DNA work.
Watson & Crick had previously made equally obtuse mistakes, including ignoring water’s role in the DNA molecule. But, determined to secure their career prospects, Watson & Crick persevered post haste.
A crucial piece of the puzzle was handed to them by John Griffiths, a mathematics postgraduate student: that nucleobases A & T paired, as did C & G.
Linus Pauling had heard that years before, on a sea cruise where Griffiths and Pauling were on the same boat. But petulant Pauling, peeved at having his vacation interrupted, ignored Griffiths’ input.
In the finale, Watson & Crick put the matching bases inside, and flipped the negative phosphorous ions so they wouldn’t touch. The result was a tight-fitting double helix that checked out.
DNA comprises a double helix of paired molecules, joined by hydrogen bonds. The helix is like a twisting ladder, each rung a bonding of 2 complementary nucleobases.
“Watson & Crick’s triumph, shortly before others hot on the same trail, came solely from the chemical and physical observations done by others, without doing any original research themselves. Obsession paid off in a Nobel prize.
Chemical Composition
All of today’s DNA, strung through all the cells of the Earth, is simply an extension and elaboration of the first molecule.” ~ American physician Lewis Thomas
The polynucleotides of DNA and RNA form a long chain built from millions of nucleotide subunits. Nucleotides form the basic structural unit of both DNA and RNA. A nucleotide has a nucleobase and sugar and phosphate groups, all glued together by ester bonds. A nucleobase is a ring-shaped molecule with a nitrogen base.
Nucleobases pair up by chemical affinity. Base pairs come in a strictly limited variety of combinations, circumscribed by chemical bonding rules: A–T and C–G for DNA, and A–U and C–G for RNA.
The larger nucleobases – adenine (A) and guanine (G) – belong to the purine chemical class. The smaller – cytosine (C) and thymine (T) and uracil (U) – are in the pyrimidine class. Whereas pyrimidines are simple ring molecules, purines have fused rings. Purines and pyrimidines are complementary by their sharing hydrogen bonds, which is particularly convenient for adaptable information storage because hydrogen bonds are easily broken.
The backbone of both DNA and RNA is provided by a phosphodiester bond: a group of strong covalent bonds between 2 5-carbon-ring sugars and a phosphate group, over 2 ester bonds.
Esters are ubiquitous organic compounds, formed by condensing an acid with an alcohol. Many lipids are fatty-acid esters of glycerol. Esters with low molecular weight are found in pheromones, the chemical compound used in scent-based communication.
DNA–RNA Differences
DNA and RNA differ in 3 main ways: 1) number of strands; 2) sugar composition; and 3) a single nucleobase difference. Each distinction indicates RNA as the precursor to DNA.
1st, whereas RNA is a single-stranded molecule, DNA is double-stranded. RNA has much shorter chains of nucleotides than DNA. Its functions are simpler.
2nd, RNA and DNA employ different sugars; a chemical signature distinction signified by R and D. RNA contains ribose (C5H10O5; H–(C=O)–(CHOH)4–H), a slightly simpler monosaccharide than DNA’s deoxyribose (C5H10O4; H–(C=O)–(CH2)–(CHOH)3–H), (actually, 2-deoxyribose). Deoxyribose is derived from ribose by the loss of an oxygen atom (reduction).
From an evolutionary viewpoint, deoxyribose is a chemical enhancement of ribose. RNA’s ribose structure is less stable than DNA’s deoxyribose because it is more prone to hydrolysis owing to the extra oxygen atom.
In this context, hydrolysis is a reaction that breaks a biopolymer down in the presence of water and an enzyme. Hydrolysis constantly occurs in cells as part of the basic reactions on sugars for metabolism and energy storage, both involving ATP.
3rd, RNA & DNA have 1 different nucleobase. RNA’s uracil (U) is an unmethylated form of DNA’s thymine (T). The other nucleobases are the same: adenine (A), cytosine (C), and guanine (G).
A methyl group is a hydrocarbon (CH3) common in many organic compounds. In biological systems, methylation is a chemical process catalyzed by enzymes, where a methyl group substitutes for a hydrogen atom. Methylation plays a role in regulating gene expression: whether and how genetic information is used.
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Unlettered Nucleobases
The letters that comprise DNA and RNA are not the only possible nucleobases. Other molecules make the grade in fitting into a double helix.
“There is much more to the code than chemical composition. The nucleic acids are but the atomic nuclei of a larger scale system of information storage. Nature cohered to a form from a myriad of considerations, including element availability, spatial arrangement, and energy tradeoffs.
Folding
Chromatin structure stabilizes and compacts the genome to package it within the nucleus. This structure also serves as a dynamic regulator of gene expression, silencing or activating transcription depending on molecular signals impinging upon it.” ~ American biochemist David Sweatt
DNA is always intricately folded: physically shortened by a factor of 10,000 or more to fit inside cells. In human chromosomes, the packing ratio can reach 10 million to 1. This is achieved via 10,000 nonoverlapping loops. Each cell distinctly packs its DNA to suit itself, following some ineffable schema.
“The variability is truly astounding. In each being unique, chromosomes are like snowflakes.” ~ American geneticist Brian Beliveau
A human cell has 1.8 meters of DNA, wound via histones to 90 micrometers (0.09 mm) of chromatin, which is the combined package of proteins and DNA that comprise genetic information, stored in the nucleus of a eukaryotic cell.
In packaging DNA in compact form, chromatin prevents damage as well as providing a ready means to regulate expression and DNA replication. Altering the efficiency of chromatin affects the employment of the genetic information contained within.
A chromatin has 120 µm of chromosomes after being freshly duplicated and condensed during mitosis. Thousands of proteins are involved in compacting DNA.
DNA is stored in a fractal Matryoshka pattern: nested self-similar globules of sequences, highly organized spatially, and systematically nested. The spatial architecture of chromosomes and other genetic structures is critical to their operation. This crucial aspect of genetics is barely understood.
In defiance of the topological complexity that characterizes folded DNA, identical sequences can recognize each other from a distance and even gather together. When bound in double-helix form, nucleobases are tucked away, hidden behind their nucleotide support structures of charged sugar and phosphate groups. A likely explanation for such sequence identification goes to conformity in shape and charge pattern, but this is an incomplete reckoning. The inherent intelligence involved in such recognition by these DNA strands remains a mystery.
Recognizing Foreign DNA
As part of the mammal innate immune system, IFI16 is a protein that recognizes foreign DNA by distinguishing it from native DNA.
DNA unfolds a bit to reveal a strand that needs to be read in order to make a bioproduct. In mammals, less than 60 base pairs are unzipped. Exposed pathogenic DNA strands are typically longer.
IFI16 inspects DNA exposures. 4 IFI16 can fit in 60 base pairs.
If longer exposed fragments are found, IFI16 congregate along the foreign DNA strands, chaining themselves together to envelop it. These filaments form a scaffold that temporarily thwarts the pathogen. IFI16 then signal for help from immune system enforcers.
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DNA folding itself contains valuable information. How genetic information is packaged has a major impact on its functionality.
Mad cow disease is technically termed bovine spongiform encephalopathy in cattle and Creutzfeldt–Jakob disease (CJD) in humans. This disease is caused by a prion: a misfolded protein acting as an infectious agent. A prion is a template macromolecule that converts other proteins to its perversity. All known prion diseases, which are currently untreatable and universally fatal, affect the structure of brain cells or other intelligence tissue.
DNA begets RNA to extract relevant information content. This structured RNA naturally folds under the influence of several environmental factors. How RNA folds affects the processes – transcription and translation – in which it is employed.
DNA, RNA, and proteins are not the only molecules where folding is essential to proper functioning. Via folding, hemoglobin acts as molecular tongs in picking up a molecule of oxygen for transport.
DNA Knots
Linear DNA is formed from various isoforms – superhelical coils, knots, and catenanes – of closed circular DNA at thermodynamic equilibrium.
Organic molecular folding is understood by applying the mathematical concepts of topology, specifically knot theory. Every molecule has an energy landscape: a set of possible conformations, with each potential spatial configuration having an associated energy level.
Atomic interactions in molecules dictate molecular conformations that take energy to maintain. The energy level ultimately relies upon hd quantum mechanical properties.
Topologically, an energy landscape has hills and valleys of energy levels for different configurations. Applying knot theory to mathematically figure an optimal conformation for a complex macromolecule is beyond daunting because the range of possible shapes is gigantic.
The chains found in biologically significant proteins are a tiny subset of those possible. Biology cohered to optimal efficiency of all things that could be considered, given inherent tradeoffs in the dynamics of folding and unfolding.
Because folding is essential to storing and retrieving the complex coding for cellular work and reproduction, geneticists first hypothesized, wrongly, that evolution favored formations with relatively simple energy landscapes. Instead, unfolding a carbon chain requires energy, whereas a folded shape is in relative energetic repose. As DNA strands spend much more time in folded stasis, it would be wasteful to use energy to maintain the folded state.
