8.3: Nucleic Acids - Comparison of DNA and RNA

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Learning Goals (ChatGPT o3-mini, 2/1/25)

 

(Learning goals written by Claude, Sonnet 4.6, Anthropic)

Chemical Modifications of DNA and RNA and Their Functional Consequences

• Explain the chemical basis and mutational consequences of spontaneous hydrolytic deamination of cytosine to uracil in DNA — tracing the mechanism by which GC→AT transitions occur if the uracil is not removed by uracil-DNA glycosylase before replication — and explain why the evolutionary addition of a methyl group to uracil to form thymine in DNA solves the repair enzyme's recognition problem (distinguishing a legitimately AU-paired base from a deamination product CG→UA) while allowing the same base-pairing geometry, connecting this to the broader principle that the DNA base alphabet was evolutionarily selected for molecular stability and informational fidelity.
• Describe the major categories of DNA mutation — including spontaneous hydrolytic deamination, replication errors (~10⁻⁸ per bp leading to ~0.1–1 mutations per genome per replication), oxidative and nitrous acid/nitrosamine-mediated deaminations, alkylating agent-induced base modifications, and large-scale chromosomal rearrangements (deletions, inversions, translocations) — and distinguish these from epigenetic modifications of DNA (5-methylcytosine) and histones (methylation, acetylation) that alter transcription without changing the primary DNA sequence, noting that these changes can be inherited across cell generations and alter phenotype through effects on chromatin structure.

Chemical Rationale for the Structural Differences Between DNA and RNA

• Explain from a chemical and evolutionary perspective why DNA lacks the 2'-OH group present in RNA — describing how the 2'-OH in RNA enables intramolecular nucleophilic attack on the adjacent phosphodiester bond (proceeding through a pentavalent phosphorus transition state) to cleave the backbone, making RNA appropriately labile, while DNA's 2'-H prevents this reaction, conferring the greater stability required for long-term genetic information storage — and connect this to the RNA world hypothesis in which the evolution of ribonucleotide reductase (which converts the 2'-OH to 2'-H) enabled the transition from RNA to DNA as the primary genetic material.
• Explain why the phosphodiester backbone — rather than more reactive ester, amide, or anhydride linkages — was evolutionarily selected for nucleic acid polymers: the sp3-hybridized phosphorus center is less electrophilic and therefore more resistant to nucleophilic attack than a carbonyl carbon, and the negative charge on the non-bridging oxygens electrostatically discourages nucleophile approach — making the phosphodiester backbone far more stable than alternative linkages while still being cleavable by the evolved enzymes (nucleases, restriction enzymes, ribozymes) that require programmed cleavage.
• Explain how deoxyribose vs. ribose ring pucker determines whether a nucleic acid can adopt B-form or A-form helices — describing how deoxyribose preferentially adopts the C2'-endo pucker (compatible with B-DNA's extended helix of 10 bp/turn and wide major groove) and can also adopt C3'-endo (forming A-DNA), while ribose is sterically constrained to only C3'-endo (due to the 2'-OH), allowing only A-type helices with fewer bp/turn, more compact geometry, and the single-stranded tertiary folding that enables RNA's diverse structural and catalytic functions — and explain how the greater conformational flexibility of deoxyribose also enables the WC↔Hoogsteen base pair equilibrium in DNA that is strongly disfavored in A-RNA.

Structural Comparison of DNA, RNA, and Proteins

• Synthesize the structural and chemical properties of DNA, RNA, and proteins into a unified framework — explaining why DNA's high negative charge density, conformational rigidity, and chemical stability make it the ideal long-term genetic information carrier (where a single base-pair change does not alter the global helical structure, preserving readability), why RNA's ability to fold into complex tertiary structures (analogous to proteins) combined with its four-base information alphabet makes it ideally suited for both catalysis (ribozymes) and transient information transfer (mRNA), and why proteins with their 20-amino acid alphabet and chemically diverse side chains (nonpolar, polar charged, polar uncharged) eventually supplanted RNA as the primary cellular catalyst — providing the chemical basis for the RNA world hypothesis in which RNA was the original macromolecule combining both informational and catalytic functions.

Now that we understand the structures of DNA and the structures and various functions of RNA, we can more fully explore how their chemical similarities and differences contribute to different functions.

Chemical modifications of DNA and RNA

Post-translational modifications of proteins alter their structural/functional properties. Likewise, intentional chemical modifications of nucleic acid bases alter both their structures and potentially their transcriptional and translational status. Figure \(\PageIndex{1}\) shows common modifications of bases in DNA.

Figure \(\PageIndex{1}\): Common modifications of bases in DNA. Matthew K.Bilyard et al. Current Opinion in Chemical Biology. Volume 57, August 2020, Pages 1-7. https://doi.org/10.1016/j.cbpa.2020.01.014. Under a Creative Commons license

Likewise, RNA is chemically modified. Figure \(\PageIndex{2}\) shows common modifications of bases in RNA. Methylation and subsequent hydroxylation to hydroxymethyl are common to both DNA and RNA. Methylation of DNA often represses the transcription of the DNA into RNA. Hence, it has huge potential to alter gene transcription. Such changes to the DNA are called epigenetic modifications. These changes can also be passed down to future generations and affect a cell's phenotype. Histone proteins involved in DNA packing into nucleosomes can also be methylated and acetylated, altering the interaction of DNA with the nucleosome core and further compaction, thereby affecting transcription.

Figure \(\PageIndex{2}\): Common modifications of bases in RNA

Chemical modification to RNA can also change the reading of the genome. The epitranscriptome refers to the collective chemical modifications to RNA, and its understanding is part of a new field, epitranscriptomics.

Mutations

A mutation can arise from the chemical modification of bases. Uracil in RNA is a demethylated form of thymine in DNA. In RNA, AU base pairs replace AT base pairs. Why is there a need for uracil in RNA? The question could be rephrased as: why is there a need for thymine, with its extra methyl group, in DNA? It's useful to think about the consequences of replacing a single H in a molecule with a -CH₃. Take HOH (i.e., water) as an example. Our bodies are over 60% water. We drink 55 liters of water each day. Yet if we drink 0.07 L of methanol (CH₃OH), half of us would die! Let's probe some consequences of the U (no -CH₃) and T (with -CH₃) changes in DNA. It can get confusing, but remember that the normal base pairs in DNA are AT, but AU base pairs also form (they are the norm in RNA). The -CH₃ substituent on thymine does not affect its base pairing.

a. Spontaneous deamination of cytosine in DNA

Why are we now discussing cytosine in DNA? One reason is that the most common mutation in DNA is a C-to-T substitution. One way this happens is through spontaneous hydrolytic deamination of cytosine in DNA to uracil, which we have presumed is found only in RNA. The mechanism for this deamination and subsequent conversion of a GC to an AT base pair is shown in Figure \(\PageIndex{3}\). The inset box shows a simplified mechanism for spontaneous deamination.

Figure \(\PageIndex{3}\): GC to AT base pair mutation on spontaneous hydrolytic deamination of cytosine in DNA.

Hence, a possible consequence of the deamination reaction is a GC-to-AT base-pair mutation if the uracil in DNA is not removed before DNA replication. Fortunately, the enzyme uracil-DNA glycosylase can remove uracils from DNA, leaving an abasic site, which can be repaired by DNA repair enzymes.

We can now ask why T, not U, is in DNA. Pretend you are a DNA repair enzyme and see a UA base pair in DNA. How can you tell whether the UA base pair is correct and intended to be there, or whether it should be a CG base pair that underwent deamination? The most common uracil-DNA glycosylases remove the uracil, whether it is across from guanine, the correct base, but which can not hydrogen bond with uracil (in the green oval in Figure \(\PageIndex{3}\)), or if it is across from adenine, the wrong base (in red oval), which is present after a round of replication. Evolution has addressed this problem by adding a methyl group to uracil to form thymine, and using that base, which pairs with adenine. Now, no decision on which base across from a uracil (guanine if the uracil arose from deamination) or across from a "uracil-like" thymine (adenine) is correct.

b. Other mutations

Since we are considering chemical modifications to DNA and mutations, giving a more expanded background on them is appropriate. In addition to mutations caused by spontaneous hydrolytic cytosine deamination, mutations can also arise from incorrect base addition during DNA replication or from chemical damage caused by radiation or chemical-modifying agents. How many mistakes in replication are made? You would be ecstatic if you received a 99% on an examination. That's not good enough for DNA replication. In Cell Biology by the Numbers, they calculate it this way. Assume the replication /repair is so good that it takes 10⁸ replications to make a mistake (an error rate of 10^-8/BP). Assume also that there are 3 x 10⁹ base pairs in the human genome. This leads to a mutation rate of 10-100 mutations/genome/generation or about 0.1-1 mutations/genome/replication. Not bad!

Figure \(\PageIndex{4}\) shows how common point mutations might randomly arise.

Figure \(\PageIndex{4}\): How common point mutations might arise randomly

Chemical agents can also cause point mutations. Figure \(\PageIndex{5}\) shows point mutations arising from oxidative deaminations (not hydrolytic) by nitrous acid/nitrosamines and from alkylating agents.

Figure \(\PageIndex{5}\): Nitrous acid/nitrosamines and alkylating agent point mutations

Figure \(\PageIndex{6}\) shows a variety of alkylating agents with mutagenic potential.

Figure \(\PageIndex{6}\): Alkylating agents with mutagenic potential.

Finally, large-scale changes in chromosome structure can also occur, as shown in Figure \(\PageIndex{7}\), usually with profound consequences.

Figure \(\PageIndex{7}\): Large scale structural rearrangements in DNA

Why DNA and RNA - A Chemical Perspective

Asking a "why" question (like above) in the sciences is inappropriate, as teleological questions are more philosophical or religious. Yet we will in this section, in part, to be in the company of Alexander Rich, who wrote a very cool article entitled "Why RNA and DNA have different Structures".

Given that RNA can express catalytic activities and can carry genetic information (some viruses have ds and ss RNA as their genomes), it has been suggested that early life might have been based on RNA. DNA would later evolve into a more secure carrier of genetic information. Inspecting the chemical properties of DNA, RNA, and proteins reveals attributes needed for their expressed functions. Let's examine each for structural features that might be important for function.

a. Why does DNA lack a 2' OH group (found in RNA), which has been replaced with hydrogen? This required the evolutionary creation of a new enzyme, ribonucleotide reductase, to catalyze the replacement of the OH group in a ribonucleotide monomer with a deoxyribose group. One possible explanation is offered in the figure below. DNA, the main carrier of genetic information, must be an extremely stable molecule. An OH present on C'2 could act as a nucleophile and attack the proximal P in the phosphodiester bond, leading to a nucleophilic substitution reaction and potential cleavage of the bond. RNA, an intermediary molecule whose concentration (at least as mRNA) should rise and fall in response to the need for a potential transcript, should be more labile to such hydrolysis. Figure \(\PageIndex{8}\) shows a possible reaction diagram for the internal cleavage of RNA. (The reaction would probably proceed with no actual intermediate, but just a transition state.

Figure \(\PageIndex{8}\): Internal cleave of RNA using the C'2-OH as an intramolecular nucleophile

b. Why do both DNA and RNA contain a phosphodiester link between adjacent monomers instead of more "traditional" links such as carboxylic acid esters, amides, or anhydrides? One possible explanation is given below. Nucleophilic attack on the sp³ hybridized P in a phosphodiester is much more difficult than for a more open sp² hybridized carboxylic acid derivative. In addition, the negative charge on the O in the phosphodiester link would decrease the likelihood of a nucleophilic attack. The negative charges on both strands in ds-DNA probably help keep the strands separated, allowing the traditional base pairing and double-stranded helical structure to be observed. The cleavage of the phosphodiester link in DNA and a hypothetical ester link is shown in Figure \(\PageIndex{9}\). Again, the reaction of the phosphodiester shows a pentavalent intermediate, but most likely proceeds directly from the transition state.

Figure \(\PageIndex{9}\): cleavage of the phosphodiester link in DNA and a hypothetical ester link

c. Why is DNA found as a repetitive double-stranded helix, but RNA is usually found as a single-stranded molecule that can form complicated tertiary structures with some dsRNA motifs?

Another reason for the absence of the 2' OH in DNA is that it allows the deoxyribose ring in DNA to pucker just the right way to allow extended ds-DNA helices (B type). The puckers in deoxyribose and ribose can be visualized as a single plane in the sugar ring, defined by the ring atoms C1', O, and C4'. If a ring atom points in the same direction as the C4'-C5' bond, the ring atom is defined as endo. If it points in the opposite direction, it is defined as exo. In the most common form of double-stranded DNA, B-DNA, the iconic extended double helix, C2' is in the endo form. It can also adopt the C3' endo form, forming another less common helix, a more open ds-A helix. In contrast, steric interference prevents ribose in RNA from adopting the 2'endo conformation. It allows only the 3' endo form, precluding the formation of extended ds-B-RNA helices but allowing more open, A-type helices.

Figure \(\PageIndex{10}\) shows another comparison between the A-RNA and B-DNA double helices and the C'3 and C'2 endo forms of the ribose

Figure \(\PageIndex{10}\): after Zhou et al. Nature Structural and Molecular Biology. doi:10.1038/nsmb.3270

Figure \(\PageIndex{5}\) shows interactive iCn3D models of the pentoses in a strand of A-RNA (413D), double-stranded, left, and B-DNA (1BNA), double-stranded, right.

C'3-endo ribose, A-RNA (413D, double stranded)	C'2 endo ribose, B-DNA (1BNA, double stranded)
Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...KPueqrBADczh26	Click the image for a popup or use this external link: https://structure.ncbi.nlm.nih.gov/i...BEn5nqsCQG2JH6

d. What about the molecular dynamics of A-RNA and B-DNA?

The information above suggests that the sugar ring of DNA is conformationally more flexible than the ribose ring of RNA. This can be inferred from the observation that dsDNA can adopt B and A forms, which requires a switch from the 2' endo in the B form to the 3'endo form in the A form. The smaller H on the 2'C would offer less steric interference with such flexibility. The rigidity of ribose is associated with a shorter 5'•3 'distance in RNA, leading to nucleotide compression into a helix with fewer base pairs per turn.

The increased flexibility in DNA allows rotation around the C1'-N glycosidic bond connecting the deoxyribose and base, allowing different orientations of AT and GC base pairs. The normal "anti" orientation allows "Watson-Crick" (WC) base pairing between AT and GC base pairs, while the altered rotation allows "Hoogsteen" (Hoog) base pairs. Figure \(\PageIndex{11}\) shows the different orientations for an AT base pair.

Figure \(\PageIndex{11}\): Xu, Y., McSally, J., Andricioaei, I. et al. Modulation of Hoogsteen dynamics on DNA recognition. Nat Commun 9, 1473 (2018). https://doi.org/10.1038/s41467-018-03516-1Creative Commons Attribution 4.0 International License. http://creativecommons.org/licenses/by/4.0/.

The Watson-Crick (WC) and Hoogsteen (HG) base pairs in B-DNA are in a dynamic equilibrium, with the equilibrium greatly favoring the WC form, as indicated by the arrows in the figure above. In a DNA:protein complex, the WC ↔ HG equilibrium can favor the WG form for AT and the GC+ form (in which the C is protonated) when those base pairs are also involved in protein recognition. They can also occur more frequently in damaged DNA. In contrast, molecular dynamics studies show that the HG base pairs A-U and GC⁺ are strongly disfavored in ds A-RNA.

One type of DNA damage is methylation at N1 of adenosine and Guanosine. This modification prevents Watson-Crick base pairing, but in DNA these modified bases can still engage in Hoogsteen base pairing, preserving the overall structure of dsDNA and its ability to stably carry genetic information. This same methylation occurs normally in post-transcriptionally modified RNA. Hence, N1 adenosine and N1 guanosine methylation prevent any base pairing in the modified RNA. These properties make DNA a better carrier of molecular information and offer another way to regulate RNA's structural and functional properties.

Hoogsteen base pairs can be found in distorted dsDNA structures (caused by protein:DNA interactions) and normal B-DNA. Figure \(\PageIndex{12}\) shows a Hoogsteen base pair between dA7 and dT37 in the MAT α 2 homeodomain:DNA complex (pdb 1K61). Note that the dA base in the Hoogsteen base pair is rotated syn (with respect to the deoxyribose ring) instead of the usual anti, allowing the Hoogsteen base pair.

Figure \(\PageIndex{12}\): Hoogsteen base pair between dA7 and dT37 in the MAT α 2 homeodomain:DNA complex (pdb 1K61)

A Structural Comparison

Now, let's review the structures adopted by the three major macromolecules: DNA, RNA, and proteins. DNA predominantly adopts the classic ds-BDNA structure, although it is wound around nucleosomes and "supercoiled" in eukaryotic cells since it must be packed into the nucleus. Prokaryotic DNA is typically packed into a more amorphous nuclear region, the nucleoid, through interactions with other proteins that also facilitate supercoiling.  It is, in effect, a dynamic molecular condensate.

The extended ds-BDNA helical form arises partly from the significant electrostatic repulsions of two strands of this polyanion (even in counter-ions). Given its high charge density, it is unsurprising that it forms complexes with positive proteins and does not adopt complex tertiary structures. RNA, conversely, can not form long B-type double-stranded helices (due to steric constraints of the 2'OH and the resulting 3'endo ribose pucker). Rather, it can adopt complex tertiary conformations (albeit with significant counterion binding to stabilize the structure) and, in doing so, form regions of secondary structure (ds-A RNA) in the form of stem/hairpin structures. Proteins, with their combination of polar charged, polar uncharged, and nonpolar side chains, offer little electrostatic hindrance to the adoption of secondary and tertiary structures. RNA and proteins can adopt tertiary structures with potential binding and catalytic sites, making them ideal catalysts for chemical reactions. Given its four-nucleotide alphabet, RNA can also carry genetic information, making it an ideal candidate for the first evolved macromolecules enabling the development of life. Proteins with abundant organic functionalities eventually supplanted RNA as a better catalyst for life. DNA, with its greater stability, would supplant RNA as the choice for the primary carrier of genetic information (Figure \(\PageIndex{13}\)):

Figure \(\PageIndex{13}\): Summary comparison of DNA, RNA, and Protein structures

A final note on the simplicity of the dsDNA structure. A mutation causing a single base pair change in DNA does not change the iconic ds-stranded DNA structure. If it did, DNA would not be a reliable molecule for storing and reading the genetic blueprint. In contrast, a single mutation in the DNA, leading to a single amino acid substitution, may yield a protein with altered structure and function. This could be deleterious or even fatal to the organism. On the other hand, the new protein structure might have functionalities that enable adaptation to new environments or support new types of reactions. Evolution would favor the latter.

Summary

(Summary written by Claude, Sonnet 4.6, Anthropic)

This chapter examines the chemical modifications of DNA and RNA, the origins and types of DNA mutations, and the fundamental chemical rationale for the structural differences between DNA, RNA, and proteins — providing a molecular framework for understanding why these three macromolecular classes have evolved their distinct structural features and biological roles.

Chemical modifications of nucleic acids are pervasive and functionally important. In DNA, the most biologically significant modification is 5-methylcytosine (5-mC), an epigenetic mark that typically represses transcription of the region it marks. The term "epigenetic" describes heritable changes in gene expression that do not alter the primary DNA sequence — these include DNA cytosine methylation and post-translational modifications of histone proteins (particularly methylation and acetylation of Lys and Arg residues on histone tails), which collectively regulate chromatin compaction and access of transcription machinery to DNA. Histone acetylation (which neutralizes the positive charge on Lys ε-amino groups, reducing histone-DNA electrostatic attraction) generally promotes transcription, while histone deacetylation and methylation are associated with transcriptional repression. In RNA, the epitranscriptome encompasses a rich collection of post-transcriptional modifications, including pseudouridine (Ψ), N6-methyladenosine (m⁶A), 2'-O-methylation, and others that regulate RNA stability, structure, splicing, and translation efficiency.

Mutations in DNA arise from multiple sources. The most common single-base mutation — C→T transition — occurs through spontaneous hydrolytic deamination of cytosine, in which water attacks the C4 position of the cytosine ring, removing the exocyclic amino group and converting cytosine to uracil. If the resulting G·U mispair is repaired correctly (G is the correct pairing partner opposite the original C, and the uracil is removed by uracil-DNA glycosylase before replication), the original G·C is restored. If uracil is not removed before replication, the new strand synthesized opposite it incorporates adenine, resulting in a permanent G·C→A·T mutation. The evolutionary solution to the problem of distinguishing a "legitimate" thymine (in a normal T·A base pair) from a mutant uracil (in a U·A base pair arising from deamination) is elegant: adding a methyl group to uracil at C5 produces thymine, which is chemically distinct from uracil (detectable by repair enzymes) but base-pairs identically with adenine. A uracil opposite guanine is unambiguously identified as a deamination product and excised; a thymine opposite adenine is correctly interpreted as the normal base. Other sources of mutation include oxidative deamination by nitrous acid or nitrosamines (converting cytosine to uracil and adenine to hypoxanthine), alkylating agents (which add methyl or other alkyl groups to ring nitrogens and exocyclic oxygens, blocking base pairing), replication errors (estimated at ~10⁻⁸ per base pair, yielding ~0.1–1 mutations per human genome per replication cycle), and large-scale chromosomal rearrangements (deletions, duplications, inversions, translocations) that typically have severe phenotypic consequences.

The chemical rationale for DNA lacking the 2'-OH centers on the consequences of intramolecular nucleophilic attack. In RNA, the 2'-OH positioned adjacent to the phosphodiester bond can donate its oxygen as a nucleophile, attacking the phosphorus in an intramolecular transesterification reaction that cleaves the backbone through a pentavalent phosphorus transition state. This makes RNA inherently more susceptible to hydrolysis — appropriate for a transient regulatory or informational molecule whose concentration should respond dynamically to cellular needs. DNA, by replacing the 2'-OH with a 2'-H, eliminates this attack pathway, conferring the much greater chemical stability required for a molecule whose primary purpose is long-term storage of genetic information across many generations. The evolution of ribonucleotide reductase — the enzyme that reduces the 2'-OH of ribonucleotides to generate deoxyribonucleotides — was a prerequisite for the transition from an RNA world to one using DNA for genetic storage.

The phosphodiester backbone was selected over seemingly more reactive alternatives (carboxylic acid esters, amides, anhydrides) because the phosphodiester linkage is far more resistant to uncatalyzed hydrolysis. The sp3-hybridized phosphorus center (in contrast to the sp2-hybridized, planar carbonyl carbon in ester and amide linkages) is less electrophilic and more sterically hindered toward nucleophilic attack. Additionally, the negative charge on the non-bridging oxygens of the phosphodiester further repels incoming nucleophiles electrostatically. These properties make phosphodiester bonds stable enough to support billions of base pairs in a genome, yet cleavable by the properly positioned active-site nucleophiles of evolved nucleases, restriction enzymes, and ribozymes.

Ribose vs. deoxyribose ring pucker explains the fundamental structural difference between RNA and DNA secondary structures. The geometry of the five-membered sugar ring is defined by whether the C2' or C3' atom deviates from the plane defined by C1', O4', and C4'. In C2'-endo (the preferred pucker of deoxyribose in B-DNA), the C2' atom points toward the base, giving a 10 bp/turn extended helix with a wide major groove and narrow minor groove — ideally suited for long-range storage of sequence information readable by proteins. In C3'-endo (the only pucker allowed by ribose due to steric clash of the 2'-OH with the C2'-endo conformation), the C3' atom points toward the base, forcing a tighter, shorter helix (A-type, 11 bp/turn, deep narrow major groove, shallow minor groove). The conformational flexibility of deoxyribose additionally enables the rotation of the purine around the N-glycosidic bond from the anti conformation (giving Watson-Crick base pairing) to the syn conformation (giving Hoogsteen base pairing), an equilibrium not available in A-RNA where the 2'-OH restricts glycosidic bond rotation. Hoogsteen base pairs in dsDNA allow DNA to accommodate certain protein-binding events and DNA damage lesions (N1-adenosine or N1-guanosine methylation can still base-pair in the Hoogsteen mode in DNA but prevents any base-pairing in RNA, illustrating how the same chemical modification has profoundly different structural consequences in the two nucleic acids).

The evolutionary logic of the three macromolecule types can thus be summarized chemically. DNA's high charge density, conformational rigidity, chemical stability (no 2'-OH, C2'-endo pucker enabling B-form helix), and structural redundancy (a single base change does not alter the overall double-helical geometry) make it the ideal long-term repository of genetic information: changes in sequence are read out in protein function without disturbing the DNA carrier. RNA combines the ability to carry sequence information (through its four-nucleotide alphabet and base-pairing capacity) with the ability to adopt protein-like tertiary structures (due to the C3'-endo ribose pucker forcing A-type helix formation, combined with non-canonical base pairing, pseudoknots, and G-quadruplexes stabilized by counter-ions), conferring both informational and catalytic capacity — supporting the RNA world hypothesis. Proteins, with their 20-amino acid alphabet offering diverse polar, charged, nonpolar, acidic, and basic side chains, provide far more chemical versatility for catalysis than RNA's four-base alphabet, explaining why proteins have largely supplanted RNA as the dominant cellular catalyst, while RNA retains critical catalytic roles in the most ancient cellular machines (the ribosome, the spliceosome, RNase P).

References

Börner, R., Kowerko, D., Miserachs, H.G., Shaffer, M., and Sigel, R.K.O. (2016) Metal ion induced heterogeneity in RNA folding studied by smFRET. Coordination Chemistry Reviews 327 DOI: 10.1016/j.ccr.2016.06.002 Available at: https://www.researchgate.net/publication/303846502_Metal_ion_induced_heterogeneity_in_RNA_folding_studied_by_smFRET

Hardison, R. (2019) B-Form, A-Form, and Z-Form of DNA. Chapter in: R. Hardison’s Working with Molecular Genetics. Published by LibreTexts. Available at: https://bio.libretexts.org/Bookshelves/Genetics/Book%3A_Working_with_Molecular_Genetics_(Hardison)/Unit_I%3A_Genes%2C_Nucleic_Acids%2C_Genomes_and_Chromosomes/2%3A_Structures_of_Nucleic_Acids/2.5%3A_B-Form%2C_A-Form%2C_and_Z-Form_of_DNA

Lenglet, G., David-Cordonnier, M-H., (2010) DNA-destabilizing agents as an alternative approach for targeting DNA: Mechanisms of action and cellular consequences. Journal of Nucleic Acids 2010, Article ID: 290935, DOI: 10.4061/2010/290935 Available at: https://www.hindawi.com/journals/jna/2010/290935/

Mechanobiology Institute (2018) What are chromosomes and chromosome territories? Produced by the National University of Singapore. Available at: https://www.mechanobio.info/genome-regulation/what-are-chromosomes-and-chromosome-territories/

National Human Genome Research Institute (2019) The Human Genome Project. National Institutes of Health. Available at: https://www.genome.gov/human-genome-project

Wikipedia contributors. (2019, July 8). DNA. In Wikipedia, The Free Encyclopedia. Retrieved 02:41, July 22, 2019, from https://en.Wikipedia.org/w/index.php?title=DNA&oldid=905364161

Wikipedia contributors. (2019, July 22). Chromosome. In Wikipedia, The Free Encyclopedia. Retrieved 15:18, July 23, 2019, from en.Wikipedia.org/w/index.php?title=Chromosome&oldid=907355235

Wikilectures. Prokaryotic Chromosomes (2017) In MediaWiki, Available at: https://www.wikilectures.eu/w/Prokaryotic_Chromosomes

Wikipedia contributors. (2019, May 15). DNA supercoil. In Wikipedia, The Free Encyclopedia. Retrieved 19:40, July 25, 2019, from en.Wikipedia.org/w/index.php?title=DNA_supercoil&oldid=897160342

Wikipedia contributors. (2019, July 23). Histone. In Wikipedia, The Free Encyclopedia. Retrieved 16:19, July 26, 2019, from en.Wikipedia.org/w/index.php?title=Histone&oldid=907472227

Wikipedia contributors. (2019, July 17). Nucleosome. In Wikipedia, The Free Encyclopedia. Retrieved 17:17, July 26, 2019, from en.Wikipedia.org/w/index.php?title=Nucleosome&oldid=906654745

Wikipedia contributors. (2019, July 26). Human genome. In Wikipedia, The Free Encyclopedia. Retrieved 06:12, July 27, 2019, from en.Wikipedia.org/w/index.php?title=Human_genome&oldid=908031878

Wikipedia contributors. (2019, July 19). Gene structure. In Wikipedia, The Free Encyclopedia. Retrieved 06:16, July 27, 2019, from en.Wikipedia.org/w/index.php?title=Gene_structure&oldid=906938498