RNA Self Replication

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RNA Self Replication

Conceptually RNA should be able to self replicate without the help of proteins. This is shown in figure 10.1. The original strand serves as a template. New base pairs arrive and form weak bonds with their complement. A can form a bond with U, and G can form a bond with C. After one replication, two complementary strands exist. Another round of replication is necessary to duplicate the original strand. The complement to the original strand is also free to make more copies. While this is still the most promising theory for life's origin, this theory seems to offer more problems than solutions. This is why the origin of life remains a mystery.

Figure 10.1: Conceptual Model for RNA Self Replication

rna-self-replication.GIF (32635 bytes)

On paper, this model is great. Nevertheless, it does not work all that well in the lab. The problems were described by Joyce and Orgel as follows:

•    Most strands of RNA are unsuitable templates. The original RNA molecule that serves as the template must contain a very high concentration of cytosine to make process 1 in figure 10.1 viable.2,3 This situation is unlikely to be met because as discussed earlier cytosine has no plausible prebiotic synthesis pathway and it decays rapidly. Nevertheless, the original strand depicted in figure 10.1 meets the high C requirement.

•    The chain will not grow correctly unless a very specific activation agent is used to activate the nucleotides. The activation agent of choice is not ATP (GTP, CTP or UTP). While life uses these, if these activation agents are used without proteins the phosphate bonds usually attach to the wrong carbon atom in ribose.2,3 ImpA, impG, impU and impC are the activation agents of choice. These activation agents contain the same side group as the amino acid histidine, which is one of the three amino acids that have not been synthesized in prebiotic experiments. Thus, it is unlikely that these activation agents where present in the primordial soup.

•    The complement of the original chain will have a high G content. This is inevitable due to the requirement for high C in the original chain. This is problematic because RNA with a high concentration of guanine tends to fold up in such a way that it cannot be an effective template for replication.2,3 Thus, the second round of growth in figure 10.1 does not happen.

•    If different isomers of ribose are present, these isomers will terminate the growing chain.2,3

Joyce and Orgel comment that “In light of the available evidence, it seems unlikely that a pair of complementary sequences can be found each of which facilitates the synthesis of the other . . . ” 3

   Just to add to the difficulties, if too many steps form in the replication ladder (complementary bonds between base pairs), then the strands will never separate.4 Furthermore, figure 10.1 is oversimplified in that it does not show that in order for the RNA strands to grow, an RNA enzyme is required to catalyze the reaction. Because a growing chain cannot catalyze its own replication, two identical RNA molecules must arise simultaneously in the soup. Each capable of replicating the other.

   A pattern is beginning to emerge for the RNA world. The RNA world is a speculative world without proteins where RNA is the most important molecule. RNA regulates all chemical reactions and contains all of the molecular knowledge for life. The pattern that is emerging is that perhaps this world is too speculative in that it may have never existed.

   Again Joyce and Orgel put it best: “Scientists interested in the origins of life seem to be divided neatly into two classes. The first, usually but not always molecular biologists, believe that RNA must have been the first replicating molecule and that chemists are exaggerating the difficulties of nucleotide synthesis . . . The second group of scientists are much more pessimistic. They believe that the de nova appearance of oligonucleotides on the primitive earth would have been a near miracle. The author’s subscribe to this latter view. Time will tell which is correct.”3

   One last point, RNA replication in the lab makes use of extensive investigator interference. Chemicals like amino acids, aldehydes, and sugars (other than ribose) are arbitrarily excluded. Very specific activation agents are used to encourage replication (ImpA for adenine, ImpG for guanine, ImpC for cytosine, and ImpU for uracil). The concentration of the chemicals (especially cytosine and ribose) is billions and billions of orders of magnitude higher than what one would expect under plausible prebiotic conditions.

   Dynamite is being used to blow the door open in figure 9.4, and the door is just too solid. It remains closed and the scientist remains trapped. Fortunately, many scientists understand this, and they no longer claim that the door is open.

How Much Knowledge is Required to Create a Ribozyme

RNA molecules capable of facilitating chemical reactions do exist. Because such RNA molecules perform a role traditionally carried out only by protein enzymes, they are called ribozymes. Ribozymes have been shown to facilitate the creation of both peptide bonds in proteins, and the bonds between phosphate and ribose in RNA. This discovery is very significant in that it means RNA can both store and implement knowledge. It also explains the popularity of RNA as the first living molecule.

   Bartel carried out a very relevant experiment. In this experiment. 65 ribozymes were isolated from a pool of 1x1015 RNA molecules. All ribozymes isolated contained at least 200 bases. This result allows for a direct calculation of the knowledge in ribozymes. If 65 sequences have some minimal enzymatic activity out of a pool containing 1015 random sequences, then one in every 15 trillion sequences is a ribozyme. Thus the molecular knowledge is as follows: knowledge = 3.32 x log (15 trillion) or 44 bits. Note that knowledge and not information is used because the 65 ribozymes were not yet optimized. The experiment also subjected the ribozymes to several rounds of selection in which only the best were chosen. Selection dramatically improved their catalytic efficiency. Thus, Bartel’s experiment proves that both information and knowledge can evolve under the guidance of natural selection.

   Given the extreme difficulties associated with synthesizing an RNA molecule containing 200 or more bases, it is unlikely that even one such molecule ever existed on the primitive earth, and 15 trillion are needed to just get 65 functional ribozymes. Furthermore, ribozymes are not self replicators. The knowledge required for self replication is certainly many orders of magnitude more than the 44 bits required for a marginally functional ribozyme. Finally, the 44 bits calculated above is in a test tube where all competing side reactions are eliminated. If the real primordial soup contains free amino acids, aldehydes, and undesirable isomers of ribose, then the 44 bits will increase by a factor similar to the increase seen for the protein insulin in chapter 5. Taking this last factor into account, the 44 bits is at least one order of magnitude too small.

Next: Molecular Knowledge in Primordial Soup

Previous: Self Replicating Peptides  

Navigation Menu Chapter 10

Chapter 10: Self Replicating Molecules (RNA and Proteins)
        A Self Replicating Peptide
        RNA Self Replication
        Molecular Knowledge in the Primordial Soup
        Self Replication and Perpetual Motion

PDF: Self Replicating Molecules and Systems (250 Kb)

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