Every biology student learns that a codon is a three nucleotide sequence found on messenger RNA that codes for one of the twenty amino acids. They also learn that this codon on the mRNA interacts with the anticodon on the tRNA during the process of translation.

Yet research has also shown that at least some codons and anticodons can also participate in the binding of their respective amino acids. My last essay shows that the codons and anticodons that do bind are neither reflective of a random sample of amino acids nor a sample of amino acids spawned in the Miller-Urey experiment. Of course, this could change, as future research may show that most amino acids can be bound by their codons or anticodons (consistent with the view that the laws of Nature may have front-loaded the appearance of the Code).

What’s more, as I write in my book, “We are not engaging in a Duck Hunt; we are going to chase the Rabbit.” For this is where the truly interesting aspect of this research emerges. If we are to follow the Rabbbit, how in the world can we explain these codon/anticodon interactions with their amino acids? Why should any codon or anticodon bind to its cognate amino acid? Is there a teleological explanation for such activity? Or must we attribute it to the Duck and interpret it as a molecular fossil from the primordial history of life?

There is indeed a teleological explanation that is suggested by one telling clue. Some amino acids bind their codons, others bind their anticodon, while others bind both. Codon and anticodon. Codon and anticodon. To me, that sounds like…..DNA. The DNA molecule is a double-helix and in a DNA molecule, every “codon” is base-paired to its “anti-codon.” So might all this binding have a functional role inside every living cell, where amino acids from binding proteins interact with their codons/anticodons in DNA form?

To check out this possibility, I simply conduct a PubMed search with the following string: “protein dna interaction codon anticodon.”

One of the articles retrieved is from Harris LF, Sullivan MR, and Popken-Harris PD and is entitled, Molecular dynamics simulation in solvent of the bacteriophage 434 cI repressor protein DNA binding domain amino acids (R1-69) in complex with its cognate operator (OR1) DNA sequence. (J Biomol Struct Dyn. 1999 Aug;17(1):1-17). Here is the abstract:

We investigated protein/DNA interactions, using molecular dynamics simulations computed between a 10 Angstom water layer model of the 434 cI Repressor protein DNA binding domain (DBD) amino acids (R1-69) and DNA of operator (OR1) and its flanks consisting of 28 nucleotide base pairs. Hydrogen bonding interactions were monitored. In addition, van der Waals and electrostatic interaction energies were calculated. Amino acids of the 434 cI repressor DNA recognition helix 3 formed both direct and water mediated hydrogen bonds at cognate codon-anticodon nucleotide base and backbone sites within the OR1 DNA major groove halfsites and flanking regions. In addition, hydrophilic amino acids within the loop between helix 3 and helix 4 have strong electrostatic attraction to codon-anticodon nucleotides located within the central nucleotides of the minor groove between the OR1 major groove halfsites. These interactions together induced significant structural changes in the operator DNA manifested by overtwisting of the central nucleotide base pairs and narrowing of the minor groove between the DNA major groove halfsites. Finally, these findings offer a code for site specific DNA recognition by the 434 cI repressor protein.

So amino acids, as part of a DNA-binding motif of a protein, have been shown to interact with their codons!

Another paper, by Harris, Sullivan, and Hatfield, entitled, Directed Molecular Evolution (Origins of Life and Evolution of the Biosphere 29: 425–435, 1999), reviews other examples of this phenomenon:

There is mounting evidence that in the case of protein:nucleic acid interactions the sequences in DNA responsible for directing the specific recognition between these two components, like those involving nucleic acid: nucleic acid interactions, are related. A code for recognition between regulatory proteins and the corresponding specific sequences in DNA to which they bind has been deciphered whereby the mechanism of recognition is determined by the stereochemical complementarity between sites on anino acid sidechains and sites on their cognate codon:anticodon nucleotide bases (Harris et al., 1990a, 1993). This notion of a recognition code between proteins and their specific DNA binding sites was initially based on the findings that the c-DNA sequences which encode amino acids in eukaryotic and prokaryotic regulatory proteins’ DNA recognition helices have a high degree of nucleotide subsequence similarity with the sequences in DNA to which they specifically bind and regulate transcription, operators or hormone response elements (Harris et al., 1990a,b, 1993).

In the following excerpt, GR stands for the glucocorticoid receptor and DBD stands for this protein’s DNA-binding domain. GRE stands for glucocorticoid response element, a region of the regulatory DNA that binds the glucocorticoid receptor:

By model building and conducting molecular dynamics simulations of the GR DBD protein in complex with its cognate GRE DNA, it was observed that amino acids within GR DBD structures encoded at the splice junctions of exons 3, 4 and 5 specifically interact with their cognate codon-anticodon nucleotides within the GRE and its flanking regions (Harris et al., 1994, 1995, 1996a,b). The interactions observed were manifest by strong electrostatic and H-bonding between amino acids of the GR DNA recognition structures and nucleotide base sites of their cognate codon-anticodons. As an example, during molecular dynamics arginine 466 of the GR DNA recognition helix shows movement and orientation of its sidechain toward its cognate codon site, AGA, within the GRE sequence (see Figures 5ad). This movement and orientation of the arginine 466 sidechain is manifest by strong electrostatic energy of attraction and the formation of H-bonds between the arginine sidechain and its codon nucleotides (see Figures 5b and 5d). Strong electrostatic attraction for cognate codon-anticodon nucleotides was also observed for other hydrophilic amino acids of the GR DNA recognition helix (see Figures 6a–f).

Thus, a purely functional (teleological) explanation for such binding has already been discovered. The genetic code, when embedded in the DNA molecule, can code for DNA:protein interactions in the regulatory regions of DNA. The researchers end their review with the following words:

There is emerging evidence that the sequences in DNA that direct protein: protein interactions are also related. If this proposal is correct, then the relationships between the sequences in DNA coding for these interactions constitute a life code of which the genetic code is only one aspect of the many related interactions encoded in DNA.