Francis Crick described the conventional genetic code as a “frozen accident,” given that once the mapping between codons and amino acids is established it becomes extremely difficult to make significant changes without wreaking havoc on every polypeptide made by the cell.1 In recent decades, scientists have come increasingly to the realization that the genetic code is not random but highly optimized, on multiple levels.
Not only is the genetic code itself fine-tuned for error minimization, but it turns out that the set of amino acids used in life is also highly optimal — that is to say, the selection is not random. In 2011, a paper was published, in which the authors compared the coverage of the standard alphabet of 20 amino acids for “size, charge, and hydrophobicity with equivalent values calculated for a sample of 1 million alternative sets (each also comprising 20 members) drawn randomly from the pool of 50 plausible prebiotic candidates.”2 They found that,
…the standard alphabet exhibits better coverage (i.e., greater breadth and greater evenness) than any random set for each of size, charge, and hydrophobicity, and for all combinations thereof. In other words, within the boundaries of our assumptions, the full set of 20 genetically encoded amino acids matches our hypothesized adaptive criterion relative to anything that chance could have assembled from what was available prebiotically.
I wrote about this paper when it came out here.
A more recent paper, published in 2017 in The FEBS Journal, argued that the set of amino acids commonly used throughout biology is fundamentally non-random.3 The authors argue that, when compared to other sets of amino acids in relation to “component atoms, functional groups, biosynthetic cost, use in a protein core or on the surface, solubility and stability,” there are very good reasons why biology uses the conventional set of amino acids and not others. He observes that “Applying these criteria to the 20 standard amino acids, and considering some other simple alternatives that are not used, we find that there are excellent reasons for the selection of every amino acid. Rather than being a frozen accident, the set of amino acids selected appears to be near ideal.”
Functional Groups
Doig notes that “the choice of functional groups is rather limited in small molecules when using only C, H, O, N or S.” Carbon-nitrogen bonds, carboxyls, hydroxyls, amides, and amines are stable chemical groups that can form electrostatic interactions and hydrogen bonds. Alternative chemical groups (such as esters, anhydrides, and nitriles) are too prone to hydrolysis in an aqueous environment. Moreover, aldehydes and ketones are too chemically reactive.
Biosynthetic Cost
Another property that determines which amino acids are used by the cell is the energetic cost of their biosynthesis in terms of glucose and ATP molecules: “For example, Leu costs only 1 ATP, but its isomer Ile costs 11. Why would life ever therefore use Ile instead of Leu, if they have the same properties?” Doig further notes that “Larger is not necessarily more expensive; Asn and Asp cost more in ATP than their larger alternatives Gln and Glu, and large Tyr costs only two ATP, compared to 15 for small Cys. The high cost of sulfur-containing amino acids is notable.”
Burial and Surface
A close-packed core of a protein (where there are few empty spaces) maximizes weak attractions between atoms (van der Waals interactions), which make the protein more stable. Thus, “A solid core is essential to stabilize proteins and to form a rigid structure with well-defined binding sites.” This means that having nonpolar side chains is important to stabilize close-packed hydrophobic cores. On the other hand, polar and charged amino acid side chains, which are exposed on a protein surface, promote solubility in the aqueous environment.
Solubility
Doig further observes that “the least soluble amino acid at pH 7 in water is Tyr, so any less soluble than this may not be acceptable.”
Stability
Doig also notes that “even with stable functional groups, some amino acids are prone to unwanted reactions, such as cyclisation or acyl transfer, that can lead to decomposition or racemisation.”
The Implications
Doig proceeds to consider each of the twenty commonly used amino acids, evaluating for each its suitability for life relative to other amino acid sets. He concludes that “There are excellent reasons for the choice of every one of the 20 amino acids and the nonuse of other apparently simple alternatives. If all else fails, one can resort to chance or a ‘frozen accident’, as an explanation.” Curiously, he fails to consider an alternative explanation, which seems to fit the evidence better, and for which we already possess independent evidence — i.e., purposeful selection by an intelligent mind.
Significantly, these data indicate that the space of usable amino acids is severely constrained. Evolutionary mechanisms would, therefore, need to explore a vast chemical space and converge on a highly optimized set. Once the canonical genetic code is established, it would be extremely difficult to change it over time, since each amino acid would be tied to specific codons, tRNAs, and aminoacyl-tRNA synthetases. Modifying the set of amino acids would thus require significant rewiring. Reassignments of the codons and amino acids would affect every polypeptide made by the cell and would wreak havoc on the translation of many different proteins. On the other hand, reducing the alphabet of amino acids significantly constrains the proteins that can be made. This, in turn, would constrain the chemistry and needed structural precision for primitive systems of DNA replication.
Intelligent Design
Intelligent agents are uniquely capable of purposefully selecting between options from a large search space. The fact that the set of twenty amino acids conventionally used in life is non-random but in fact highly optimized is not surprising on the hypothesis that their selection was by an intelligent mind. On the other hand, they are wildly surprising on the hypothesis that it arose by unguided processes. In view of this overwhelmingly top-heavy likelihood ratio, these findings point to teleology as being the best explanation.
Notes
- Crick FH. The origin of the genetic code. J Mol Biol. 1968 Dec;38(3):367-79. doi: 10.1016/0022-2836(68)90392-6. PMID: 4887876.
- Philip GK, Freeland SJ. Did evolution select a nonrandom “alphabet” of amino acids? Astrobiology. 2011 Apr;11(3):235-40. doi: 10.1089/ast.2010.0567. Epub 2011 Mar 24. PMID: 21434765.
- Doig AJ. Frozen, but no accident — why the 20 standard amino acids were selected. FEBS J. 2017 May;284(9):1296-1305. doi: 10.1111/febs.13982. Epub 2017 Jan 13. PMID: 27926995.