|MadSci Network: Biophysics|
To whom it may concern, The question was, how is DNA better suited than RNA to carry genetic information. Unfortunately, this is almost a philosophical question, since there really is no way of knowing for certain how the roles of DNA and RNA evolved. There may not BE an answer. Our evolutionary description of the role of DNA and RNA in biology comes from a number of observations, though we may never be able to say for certain how evolution has selected these functions. I'll assume you know enough about the chemistry of RNA and DNA to bypass some of the normal introductory discussion. The only chemical difference between RNA and DNA is the presence of 2'OH on the ribose of RNA. This has pronounced effects on the structure and stability of RNA as compared to DNA. The most obvious changes observed between ribose and deoxyribose sugars are in the distribution of sugar puckers; C3'-endo versus C2'-endo conformations dominate duplex RNA and DNA, respectively (Note that single deoxy- or ribonucleotides generally have a C2'-endo conformation, though there is distribution of sugar conformations for isolated nucleotides). In double-helical regions of nucleic acids, the sugar conformation affects the major and minor groove widths, the rise per base pair, the average axial diameter, and the twist angle. In general, the 2'-OH is involved in hydrogen-bonding interactions with water, in duplex RNA regions, so this does not directly impact the structure or distribution of structures on its own. In short, the presence or absence of the 2'-OH in RNA and DNA has immediate though indirect effects on the structure of nucleic acids. In terms of thermodynamic stability, it is known that duplex RNA is more stable than duplex DNA. The stability of double-stranded nucleic acids can be described a number of ways. In addition to cross-strand hydrogen bonding interactions between bases, the stacking interactions between successive base pairs contributes significantly to the measured stability of short regions of either DNA or RNA. It is known that stabilization from stacking interactions comes from nearest neighbor interactions, and does not propagate beyond the adjacent base pairs. (In fact, you can use published thermodynamic values to predict the stability of a particular duplex RNA or DNA sequence with surprising accuracy). The bottom line, using base pairing rules, is that short regions of RNA are more stable than short regions of DNA, by roughly 0.5 kcal/mol/base pair. Another measure of nucleic acid stability is the persistence length, a bulk property of long double-stranded nucleic acids. The persistence length is a measure of the rigidity of a polymer, simply the average distance over which a DNA or RNA molecule behaves like a rod. If you think of a long polymer (1000 base pairs of DNA, or more), it will be rigid over short regions and can be approximated by a perfect double-helix; over the entire length of the chain, it will tend to bend. The persistence length can be thought of as an arbitrary chain length over which the polymer behaves like a rigid rod. For DNA, the persistence length is approximately 450-500 angstroms; for RNA, the persistence length is on the order of 700-750 angstroms, roughly 1.5 times as rigid as DNA. So the bulk properties of DNA and RNA again indicate that RNA is more stable than DNA. Now, consider the conformations of natural RNA and DNA molecules, in particular comparing ribosomal RNA versus genomic DNA. As you know, genomic DNA exists in a double-helical conformation across its entire length. (Note that single-stranded DNA viruses are an exception, only in the case of how the DNA is packaged; the functional form of viral DNA in infected cells is also in the duplex form). On the other hand, structured RNA molecules are comprised of short double-stranded regions (between 4 and 10 base pairs), interspersed by non-helical regions, either bulges, internal loops or hairpin loops. (Note the exception of messenger RNA which is in generally single-stranded; in fact, most mRNA sequences can adopt various base-pairing schemes, but are held in the single-stranded conformation by RNA binding proteins, facilitating ribosomal translation). In short, stretches of duplex DNA are long and contiguous; duplex regions of RNA are short and interrupted. The structural differences between duplex RNA and DNA should give you a clue why this pattern is observed. Proteins that interact with DNA and RNA must be able to bind uniquely to a particular sequence; thus proteins use the nucleotide bases for specificity. The minor groove in either RNA or DNA is accessible to proteins, but the hydrogen bonding donors and acceptors presented by either G-C or A-T(U) bases are very similar, making sequence-specific recognition of the minor groove impossible. For DNA binding proteins, sequence-specific protein interactions typically occur in the major groove of the duplex DNA. However, the major groove of RNA is too deep and narrow to permit facile access to proteins. It is generally observed that sequence-specific RNA:protein interactions occur in non-base paired regions; the internal loops, bulges, and hairpin loops, and perhaps the closing base pairs, are targets for sequence specific protein recognition. This is particularly important for functional RNA molecules: ribosomal RNAs, transfer RNAs, small nuclear RNAs, those molecules that have enzymatic activity that require proteins as co-factors. These same RNAs also form complex tertiary structures; knotted looking structures where long-range RNA-RNA contacts are often observed. The role of the 2'OH in either RNA:protein or RNA:RNA interactions is prominent, and well documented for many systems that have been studied in detail, indicating its primary role is as a handle for additional hydrogen-bonding interactions that would not be possible in the case of DNA. To put it another way, the main function of DNA we observe is one of information storage. The proteins that interact with DNA do so transiently, over the life-cycle of the molecule, and only interact with short regions through direct major groove contacts. Though duplex RNA tends to be more stable, the structural features of DNA allow it to be efficiently packaged when it is not being replicated or translated. (If DNA were more rigid than RNA, it would be more costly both energetically and spatially to use as the storage material). RNA structure is more diverse and inconsistent; the higher stability of RNA allows for non-helical regions to exist without disrupting the entire molecule. Also, it means that DNA-binding proteins and RNA-binding proteins have evolved entirely different mechanisms through which they interact with their preferred targets. The main argument I can make from you stems from the idea of the "RNA World", that is the argument that RNA, not DNA, was the first pre-biotic molecule. Life had to start somewhere, right? The simplest requirements for the first pre-biotic molecule are that they can catalyze reactions, store information, and be self-replicating. It should be obvious to you that, evolutionarily, proteins come after RNA or DNA, and are therefore not a candidate; since each amino acid is coded by three nucleotide bases, and protein synthesis in the ribosome requires incoming amino acids to be linked to tRNAs; basically, proteins did not come before RNA. (There are more arguments against proteins being the pre-biotic molecule, but that's not your question). Both DNA and RNA are basically the same in their capacity to store information. It wasn't until Tom Cech at the University of Colorado, Boulder discovered the first catalytic RNA molecule in 1981 that we could begin to make an argument for RNA. Since then, researchers have demonstrated a range of catalytic functions for RNA molecules including self-replication, peptidyl-transfer reactions (linking an amino acid to RNA), cleavage reactions (both forward and backwards), and DNA polymerization. These enzymatic functions do not require any protein; they do however require the 2'OH for catalysis, as well as anchoring long range RNA:RNA interactions required for stabilizing the catalytic RNA. These functions have not been demonstrated for DNA. Again, the argument for RNA being the first pre-biotic molecule are much longer than I've presented, but you get the idea. These arguments are in part based on the structural and functional differences between RNA and DNA outlined above. Note too that deoxyribonucleotides are synthesized from ribonucleotides through a single reduction reaction; our cells spend a tremendous amount of energy making RNA precursors through very complex pathways, yet DNA precursors are generated from RNA precursors through a single reaction. We can then argue that life began with RNA, and added in DNA as a functional molecule much later. Lastly, ask yourself how evolution would have proceeded from there. If RNA is the first functional molecule, why use DNA (or proteins) at all? Why are we not just RNA beings? Given that > 99% of our metabolic reactions are mediated by proteins, suggesting that the functional diversity of RNA as catalysts may be limited. We can guess that proteins are simply more acrobatic in terms of the kinds of reactions they can catalyze, with new enzymes evolving out of protein as their functions were needed. The evolution of DNA as a storage medium may have to do with a need to compartmentalize a cell. Life requires that a cell be able to replicate itself, so the cell must contain all the necessary information for the cell's life cycle. We can guess that it is more efficient to separate the functions we observe for DNA and RNA by separating them chemically. Their structural and energetic differences may have meant that different classes of proteins would evolve to interact with either DNA or RNA; thus replication machinery would not interact with ribosomal machinery or vice versa. The added bonus of DNA being more flexible than RNA might be responsible for the fact that DNA can be more readily packaged and protected from degradation when certain stages of a cell's life cycle are dormant. In summary, DNA is not necessarily better suited to carry genetic information than RNA, it is more likely that RNA was better suited to be the prebiotic molecule and that RNA is better suited for other functions that DNA may not be able to perform. The function of DNA as a receptacle for genetic information is likely to have evolved after the various functions of RNA were firmly in place. For additional reading, check out the following textbooks, or refer to any introductory level biochemistry or molecular biology textbook: "Biochemistry" 4th ed., Lubert Stryer, New York: W.H. Freeman, QP514.2.S66 1995 "Genes VII", Benjamin Lewin, New York: Oxford University Press, QH430.L487 1999 "The RNA World: the nature of modern RNA suggests a prebiotic RNA", R. F. Gesteland, T. R. Cech, eds., New York: Cold Spring Harber Laboratory Press, QP623.R6 1999 I hope this helps (and in the future, please don't forget to supply your name so myself or other moderators can address your questions personally). Regards, Dr. James Kranz University of Pennsylvania Steve Mack adds: The chemical difference between RNA and DNA (the absence of the 2' hydroxyl group) makes DNA a good permanent information storage molecule, while RNA is used for temporary information storage. Because ribose has both 2' and 3' hydroxyl groups, the 2' hydroxyl can "attack" the phosphodiester bond in the presence of hydroxyl radicals, which results in the phosphate backbone being broken. This reaction can occur spontaneously at neutral pH and is called auto-catalytic clevage. Because DNA does not have a 2' hydroxyl group, DNA molecules cannot undergo auto-catalytic clevage, and are therefore much more stable than RNA. In other words, the presence of the 2' hydroxyl gives RNA molecules have a significnatly shorter half-life than DNA molecules, which makes RNA much less useful as a long-term information storage molecule.
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