Life on Earth builds genetically encoded proteins by using a standard alphabet of just 20 L-α-amino acids, although many others were available to life's origins and early evolution. To better understand the causes of this foundational evolutionary outcome, we extend previous analyses which have identified a highly unusual distribution of biophysical properties within the set used by life. Specifically, we use a heuristic search algorithm to identify other sets of amino acids, from a library of plausible alternatives, that emulate life's signature. We find that a subset of amino acids seems predisposed to forming such sets. We present other examples of such alphabets under various assumptions, along with analysis and reasoning about why each might be simplistic. We do so to introduce the central, open question that remains: while fundamental biophysics related to protein folding can potentially reduce a library of 1054 possible amino acid alphabets by 7 orders of magnitude, the framework of assumptions that does so leaves a further 1045 possibilities. It is therefore tempting to ask what additional assumptions can further reduce these 45 orders of magnitude? We thus conclude with a focus on library and alphabet construction as a useful target for subsequent research that may help future science speak with more confidence about what an alien amino acid alphabet would look like and why.
Get full access to this article
View all access options for this article.
References
1.
AgasheVR, ShastryMCR, UdgaonkarJB. Initial hydrophobic collapse in the folding of Barstar. Nature, 1995; 377(6551):754–757; doi: 10.1038/377754a0.
2.
AponteJC, ElsilaJE, HeinJE, et al.Analysis of amino acids, hydroxy acids, and amines in CR chondrites. Meteorit Planet Sci, 2020; 55(11):2422–2439; doi: 10.1111/maps.13586.
BertholdMR, CebronN, DillF, et al.KNIME: The Konstanz Information Miner. In Data Analysis, Machine Learning and Applications. (Preisach C, Burkhardt H, Schmidt-Thieme L, et al. eds.) Studies in Classification, Data Analysis, and Knowledge Organization Springer: Berlin, Heidelberg,, 2008; pp 319–326; doi: 10.1007/978-3-540-78246-9_38.
5.
Bornberg-BauerE, HlouchovaK, LangeA. Structure and function of naturally evolved de novo proteins. Curr Opin Struct Biol, 2021; 68:175–183; doi: 10.1016/j.sbi.2020.11.010.
6.
Cleaves IIHJ. The origin of the biologically coded amino acids. J Theor Biol, 2010; 263(4):490–498; doi: 10.1016/j.jtbi.2009.12.014.
7.
CrickF. Central Dogma of Molecular Biology. 1970; 3.
8.
DasGuptaD, KaushikR, JayaramB. From Ramachandran maps to tertiary structures of proteins. J Phys Chem B, 2015; 119(34):11136–11145; doi: 10.1021/acs.jpcb.5b02999.
9.
DayhoffMO, SchwartzRM, OrcuttBC. 22 A model of evolutionary change in proteins. Atlas of Protein Sequence and Structure, 1978; 5:345–352.
10.
DoolittleWF. Making the most of clade selection. Philosophy of Science, 2017; 84(2):275–295; doi: 10.1086/690719.
11.
ForsytheJG, YuS-S, MamajanovI, et al.Ester-mediated amide bond formation driven by wet–dry cycles: A possible path to polypeptides on the prebiotic Earth. Angew Chem Int Ed Engl, 2015; 54(34):9871–9875; doi: 10.1002/anie.201503792.
12.
FreelandS. “Terrestrial” amino acids and their evolution. In Amino Acids, Peptides and Proteins in Organic Chemistry. John Wiley & Sons, Ltd: Weinheim,, 2009; pp 43–75; doi: 10.1002/9783527631766.ch2.
13.
Frenkel-PinterM, Haynes JWC M, et al.Selective incorporation of proteinaceous over nonproteinaceous cationic amino acids in model prebiotic oligomerization reactions. Proc Natl Acad Sci USA, 2019; 116(33):16338–16346; doi: 10.1073/pnas.1904849116.
14.
GardnerPP, HollandBR, MoultonV, et al.Optimal alphabets for an RNA world. Proc R Soc Lond B Biol Sci, 2003; 270(1520):1177–1182; doi: 10.1098/rspb.2003.2355.
15.
GlavinDP, DworkinJP, AubreyA, et al.Amino acid analyses of Antarctic CM2 meteorites using liquid chromatography–time of flight–mass spectrometry. Meteorit Planet Sci, 2006; 41(6):889–902; doi: 10.1111/j.1945-5100.2006.tb00493.x.
16.
HiggsPG, PudritzRE. A thermodynamic basis for prebiotic amino acid synthesis and the nature of the first genetic code. Astrobiology, 2009; 9(5):483–490; doi: 10.1089/ast.2008.0280.
17.
HoshikaS, LealNA, KimM-J, et al.Hachimoji DNA and RNA: A genetic system with eight building blocks. Science, 2019; 363(6429):884–887; doi: 10.1126/science.aat0971.
18.
IlardoM, MeringerM, FreelandS, et al.Extraordinarily adaptive properties of the genetically encoded amino acids. Sci Rep, 2015; 5(1):9414; doi: 10.1038/srep09414.
19.
IlardoM, BoseR, MeringerM, et al.Adaptive properties of the genetically encoded amino acid alphabet are inherited from its subsets. Sci Rep, 2019; 9(1):12468; doi: 10.1038/s41598-019-47574-x.
20.
JukesTH. Arginine as an evolutionary intruder into protein synthesis. Biochem Biophys Res Commun, 1973; 53(3):709–714; doi: 10.1016/0006-291x(73)90151-4.
21.
KauzmannW. Some factors in the interpretation of protein denaturation. In Advances in Protein Chemistry. (Anfinsen CB, Anson ML, Bailey K, et al. eds.) Academic Press, New York;, 1959; pp 1–63; doi: 10.1016/S0065-3233(08)60608-7.
22.
KhoranaHG, BüuchiH, GhoshH, et al.Polynucleotide synthesis and the genetic code. Cold Spring Harb Symp Quant Biol, 1966; 31:39–49; doi: 10.1101/SQB.1966.031.01.010.
23.
LimWA, SauerRT. The role of internal packing interactions in determining the structure and stability of a protein. J Mol Biol, 1991; 219(2):359–376; doi: 10.1016/0022-2836(91)90570-V.
24.
LongoLM, LeeJ, BlaberM. Simplified protein design biased for prebiotic amino acids yields a foldable, halophilic protein. Proc Natl Acad Sci USA, 2013; 110(6):2135–2139; doi: 10.1073/pnas.1219530110.
25.
LongoLM, DespotovićD, Weil-KtorzaO, et al.Primordial emergence of a nucleic acid-binding protein via phase separation and statistical ornithine-to-arginine conversion. Proc Natl Acad Sci USA, 2020; 117(27):15731–15739; doi: 10.1073/pnas.2001989117.
26.
LuY, FreelandS. On the evolution of the standard amino-acid alphabet. Genome Biol, 2006; 7(1):102; doi: 10.1186/gb-2006-7-1-102.
27.
LukashenkoNP. Expanding genetic code: Amino acids 21 and 22, selenocysteine and pyrrolysine. Russ J Genet, 2010; 46(8):899–916; doi: 10.1134/S1022795410080016.
28.
Mayer-BaconC, FreelandSJ. A broader context for understanding amino acid alphabet optimality. J Theor Biol, 2021; 520:110661; doi: 10.1016/j.jtbi.2021.110661.
29.
Mayer-BaconC, YirikMA. Curation of computational chemical libraries demonstrated with alpha-amino acids. J Vis Exp, 2022;(182):e63632; doi: 10.3791/63632.
30.
Mayer-BaconC, AgbohaN, MuscalliM, et al.Evolution as a guide to designing xeno amino acid alphabets. Int J Mol Sci, 2021; 22(6):2787; doi: 10.3390/ijms22062787.
31.
Mayer-BaconC, MeringerM, HavelR, et al.A closer look at non-random patterns within chemistry space for a smaller, earlier amino acid alphabet. J Mol Evol, 2022; 90(3):307–323; doi: 10.1007/s00239-022-10061-5.
32.
MeringerM, CleavesHJ, FreelandSJ. Beyond terrestrial biology: Charting the chemical universe of α-amino acid structures. J Chem Inf Model, 2013; 53(11):2851–2862; doi: 10.1021/ci400209n.
33.
MillerSL. A production of amino acids under possible primitive Earth conditions. Science, 1953; 117(3046):528–529.
34.
PaceNR. The universal nature of biochemistry. Proc Natl Acad Sci USA, 2001; 98(3):805–808; doi: 10.1073/pnas.98.3.805.
35.
ParkerGA, SmithJM. Optimality theory in evolutionary biology. Nature, 1990; 348(6296):27–33; doi: 10.1038/348027a0.
36.
PhilipGK, FreelandSJ. Did evolution select a nonrandom “alphabet” of amino acids?. Astrobiology, 2011; 11(3):235–240; doi: 10.1089/ast.2010.0567.
37.
RobsonB, PainRH. Analysis of the code relating sequence to conformation in proteins: Possible implications for the mechanism of formation of helical regions. J Mol Biol, 1971; 58(1):237–257; doi: 10.1016/0022-2836(71)90243-9.
38.
RonnebergTA, LandweberLF, FreelandSJ. Testing a biosynthetic theory of the genetic code: Fact or artifact?. Proc Natl Acad Sci USA, 2000; 97(25):13690–13695; doi: 10.1073/pnas.250403097.
39.
SalamatovaE, CunhaAV, BloemR, et al.Hydrophobic collapse in N-methylacetamide–water mixtures. J Phys Chem A, 2018; 122(9):2468–2478; doi: 10.1021/acs.jpca.8b00276.
40.
SatoshiA. Experimental test of plausible reduced amino acid sets in primordial proteins. Viva Origino, 2020; 48(3):4; doi: 10.50968/vivaorigino.48_4.
41.
SzathmáryE, SmithJM. Four letters in the genetic alphabet: A frozen evolutionary optimum?. Proc R Soc Lond B Biol Sci, 1991; 245(1313):91–99; doi: 10.1098/rspb.1991.0093.
42.
Tarcsay Á. Pushing the limit of logP prediction accuracy: ChemAxon's results for the SAMPL 6 blind challenge. ChemAxon 2021. Available from: https://chemaxon.com/blog/news/cxn-logp-prediction-sampl-6 [Last accessed 10/31/2022].
43.
TretyachenkoV, VymětalJ, NeuwirthováT, et al.Modern and prebiotic amino acids support distinct structural profiles in proteins. Open Biology, 2022; 12(6):220040; doi: 10.1098/rsob.220040.
44.
TrifonovEN. Consensus temporal order of amino acids and evolution of the triplet code. Gene, 2000; 261(1):139–151; doi: 10.1016/s0378-1119(00)00476-5.
45.
WeberAL, MillerSL. Reasons for the occurrence of the twenty coded protein amino acids. J Mol Evol, 1981; 17(5):273–284; doi: 10.1007/BF01795749.
46.
ZhouAX-Z, ShengK, FeldmanAW, et al.Progress toward eukaryotic semisynthetic organisms: Translation of unnatural codons. J Am Chem Soc, 2019; 141(51):20166–20170; doi: 10.1021/jacs.9b09080.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
