ARTICLE HISTORY Received 22 August 2016 Accepted 5 September 2016 ABSTRACT Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the genetic code, which takes into account current knowledge of the decoding process, including the complex nature of interactions between mRNA, tRNA and rRNA that take place during protein synthesis on the ribosome, and it also better reflects the evolution of the code. The new asymmetrical circular genetic code has a number of advantages over the traditional codon table and the previous circular diagrams (with a symmetrical/clockwise arrangement of the U, C, A, G bases). Most importantly, all sequence co-variances can be visualized and explained based on the internal logic of the thermodynamics of codon-anticodon interactions.

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The “periodic table” of the genetic code: A new
way to look at the code and the decoding process
Anton A. Komar
To cite this article: Anton A. Komar (2016) The “periodic table” of the genetic code: A
new way to look at the code and the decoding process, Translation, 4:2, e1234431, DOI:
10.1080/21690731.2016.1234431
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2. PERSPECTIVES
The “periodic table” of the genetic code: A new way to look at the code and the
decoding process
Anton A. Komara,b,c
a
Center for Gene Regulation in Health and Disease and Department of Biological, Geological and Environmental Sciences, Cleveland State
University, Cleveland, OH, USA; b
Department of Biochemistry and Center for RNA Molecular Biology, Case Western Reserve University,
Cleveland, OH, USA; c
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
ARTICLE HISTORY
Received 22 August 2016
Accepted 5 September 2016
ABSTRACT
Henri Grosjean and Eric Westhof recently presented an information-rich, alternative view of the
genetic code, which takes into account current knowledge of the decoding process, including the
complex nature of interactions between mRNA, tRNA and rRNA that take place during protein
synthesis on the ribosome, and it also better reflects the evolution of the code. The new
asymmetrical circular genetic code has a number of advantages over the traditional codon table
and the previous circular diagrams (with a symmetrical/clockwise arrangement of the U, C, A, G
bases). Most importantly, all sequence co-variances can be visualized and explained based on the
internal logic of the thermodynamics of codon-anticodon interactions.
KEYWORDS
aminoacyl-tRNAs; circular
genetic code diagram;
energetics of codon-
anticodon interactions;
genetic code; decoding;
genetic code evolution
The genetic code describes the correspondence between
the sequence of a given nucleotide triplet in an mRNA
molecule, called a codon, and the amino acid that it
directs to be added to the growing polypeptide chain dur-
ing protein synthesis. Decoding, or translation, of
mRNAs is performed by ribosomes, with addition of
each new amino acid to the growing chain involving a
cycle of complex reactions consisting of several major
steps.1-3
Placement of the initiator tRNA in the ribosomal
P-site (directed by the initiation/AUG codon) sets the
reading frame for all subsequent incoming aminoacyl-
tRNAs (aa-tRNAs) required for decoding of the message.
The next aa-tRNA binds to the ribosomal A-site by form-
ing base-pairs with the next codon in the mRNA. The
specificity is such that perfect Watson–Crick base pairs
are usually observed between the first 2 nucleotides in the
codon and those in the anticodon, but altered base pair-
ing is possible at the third, so-called “wobble,” position.
Wobbling occurs because the conformation of the tRNA
anticodon loop permits flexibility at the first base of the
anticodon.1-3
In the next step, if acceptable codon–anti-
codon base pairing has been established between the
mRNA and the incoming aa-tRNA, decoding is accom-
panied by a peptide bond formation between the incom-
ing amino acid and the previous amino acid.1-3
Note that
this is a simplified overview of the process, which involves
many additional/intermediate steps, which will not be
considered here.
The genetic code is nearly universal, meaning that
in almost all living organisms, the identity of the
amino acid encoded by a given triplet codon is the
same.4,5
With 4 bases (A, G, U, and C), there are 64
possible triplet codons; 61 sense (encoding amino
acids) and 3 nonsense (UAA, UAG, and UGA, so-
called stop codons that direct termination of transla-
tion). In most organisms, there are 20 common amino
acids used in protein synthesis; thus, the genetic code
is redundant with most amino acids being encoded by
more than one codon. Only two amino acids (Met and
Trp) are encoded by just a single codon in most of the
organisms (although exceptions to this rule do exist4,5
).
Phe, Tyr, His, Gln, Asn, Lys, Asp, Glu, and Cys are
each encoded by 2 distinct codons, which in each case
are identical at positions 1 and 2 but different in posi-
tion 3 (for example, Phe is encoded by UUU and
UUC) (Fig. 1A). Ile is encoded by a group of 3 codons
and Val, Pro, Thr, Ala, and Gly are each specified by a
group of 4 codons; these also differ only at position 3
within a group. The greatest degree of redundancy
exists for Leu, Ser and Arg, which are each encoded by
CONTACT Anton A. Komar a.komar@csuohio.edu The Center for Gene Regulation in Health and Disease, Cleveland State University, 2121 Euclid Ave.,
Cleveland, OH 44115, USA.
© 2016 Taylor & Francis
TRANSLATION
2016, VOL. 4, NO. 2, e1234431 (4 pages)
http://dx.doi.org/10.1080/21690731.2016.1234431

3. 6 codons (4 in one group and 2 in another group, again
with groups defined as being identical at positions 1
and 2) (Fig. 1A). The etiology of this pattern of
redundancy is not entirely clear, but is thought to be
related to co-evolution of the genetic code and amino
acids, with the appearance of the modern group of 20
Figure 1. Genetic code diagrams. (A) Schematic representation of the conventional (rectangular) genetic code table. (B) Asymmetrical
circular genetic code diagram developed by Grosjean and Westhof 10
(adapted with permission from the authors and Oxford University
Press) C, G, U, A bases arranged clockwise at the right side of the circular diagram and anti-clockwise at the left side of the diagram. The
most thermodynamically stable G/C-rich codons are placed at the top of the circle while “weaker” A/U-rich codons are at the bottom
and mixed codons appear in the mid-sections on the left and the right sides of the circle. This asymmetrical representation of the
genetic code illustrates the role of chemical energetics in decoding, with clear segregation between all GC-rich 4 codon families (unsplit;
all four codons identical at positions 1 and 2 encoding the same amino acid) and all AU-rich smaller codon families (split 2:2 or 3:1). The
new representation also highlights the significance of tRNA anticodon hairpin modifications (especially U34) aimed at fine-tuning
codon-anticodon base-pairing binding capacity for optimal and uniform translation. Arrows on the left and the right side of the diagram
highlight characteristic changes associated with the code evolution. The strengths of the codon-anticodon base pairing interactions are
color coded. Strong GC-rich codon-anticodon triplets are highlighted in cyan, while weaker UA pairs are shown in pink and the mixed
codon-anticodon triplets are shown on a white background for both (A) and (B).
e1234431-2 A. A. KOMAR

4. (C2) amino acids (additional 2 amino acids include
selenocysteine and pyrrolysine that are decoded via
the UGA an UAG stop codons, respectively) evolving
from a relatively small number of early/prebiotic
amino acids (such as e.g. Gly, Ala, Asp and Val) which
can be also synthesized via pathways with only a few
steps (for a review see ref. 6). New amino acids added
in evolution to the initial group of early amino acids
may in some cases have taken over codons previously
assigned to their precursors. Thus, in the conven-
tional/standard codon table7-9
(Fig. 1A) with blocks of
4 codons identical in positions 1 and 2 but containing
either U, C, A or G in position 3, appearance of new
amino acids led to subdivision of larger codon blocks
into smaller ones (for example, the GAx block being
subdivided/split to encode Asp with GAU and GAC
and Glu with GAA and GAG. While fundamentally
correct and accepted as quasi-universal, this standard
codon table does not fully represent the genetic code
and its evolution, as it doesn’t take into account all
aspects of the decoding process such as, for example,
the thermodynamics of codon-anticodon interactions
and the influence of tRNA modifications on such
interactions.
In a recent issue of Nucleic Acids Research, Henri
Grosjean and Eric Westhof presented10
a more infor-
mation-rich, alternative view of the genetic code table
(Fig. 1B). This representation takes into account cur-
rent knowledge of the decoding process, including the
complex nature of interactions between mRNA, tRNA
and rRNA that take place during protein synthesis on
the ribosome, and it also better reflects the evolution
of the code.10
Recent progress in deciphering the
structure and function of the ribosome as well as iden-
tifying the functional significance of modified nucleo-
tides in tRNAs has revealed the intricate complexity of
the decoding process.10
In particular, it was found that
third position “wobbling” can occur in several non-
canonical ways depending on specific tRNA modifica-
tions and that these modifications (especially in the
anticodon hairpin) serve to maintain optimal stability
of complementary codon–anticodon pairs.10
Incorpo-
rating and capitalizing on many previous observations
and representations of the code (including previous
circular genetic code diagrams10-12
), the work of
Grosjean and Westhof highlights the importance of
numerous “hidden” aspects of the decoding process
and presents a visually appealing decoding table that
takes into account multiple structural aspects of
translation and chemical interactions that govern the
process. This improvement on the standard codon
table(s) is reminiscent of the “evolution” of the peri-
odic table of elements. In 1789, Antoine Lavoisier
published the first list/table of 33 chemical elements,
grouping them according to their basic properties into
gases, metals, nonmetals, and earths.13
This first revo-
lutionary description gave a comprehensive overview
of basic chemical elements, but didn’t possess predic-
tive power. The periodic table of chemical elements
published by Dmitri Mendeleev in 186914
not only
better illustrated periodic trends in the properties of
the then-known chemical elements, but also allowed
prediction of properties of elements yet to be discov-
ered. In their new representation of the genetic code
table, Grosjean and Westhof arranged each codon cor-
responding to the 20 canonical amino acids on a circle
based on the sequence of the codon/anticodon triplet
(Fig. 1B). Quadrants of the circle are assigned to
codons with G, C, A or U in the first codon position
and then are further subdivided as a function of the
base in the second and third positions. The most ther-
modynamically stable G/C-rich codons are placed at
the top of the circle while “weaker” A/U-rich codons
are placed at the bottom and mixed codons appear in
the mid-sections on the left and the right sides of the
circle (Fig. 1B). This asymmetrical representation of the
genetic code illustrates the role of chemical energetics
in decoding, with clear segregation between all GC-rich
4 codon families (unsplit; all four codons identical at
positions 1 and 2 encoding the same amino acid) and
all AU-rich smaller codon families (split 2:2 or 3:1).
The new representation also highlights the significance
of tRNA anticodon hairpin modifications (especially
U34) aimed at fine-tuning codon-anticodon base-pair-
ing binding capacity for optimal and uniform transla-
tion. This led the authors to the important conclusion
that during genetic code expansion, optimal stability of
complementary codon–anticodon pairs likely served as
the main force driving its evolution. It also provides an
explanation for the observed nature of codon reassign-
ments most often found within split AU-rich codon
families. Thus, starting with GC-rich triplets coding for
simple/early amino acids (like Gly, Ala, Pro), the code
evolved to include AU-rich codons specifying the
amino acid products of new, more complex biosyn-
thetic machineries. This was accompanied by co-evolu-
tion of aminoacyl-tRNA synthetases and tRNA
modification enzymes.
TRANSLATION e1234431-3

5. The new asymmetrical circular genetic code dia-
gram developed by Grosjean and Westhof has a num-
ber of advantages over the traditional codon table and
the previous circular diagrams (with a symmetrical/
clockwise arrangement of the U, C, A, G bases11,12
).
Perhaps most importantly, all sequence co-variances
can be visualized and explained based on the internal
logic of the thermodynamics of codon-anticodon
interactions.10
This circular code diagram clearly indi-
cates that the code is not a “frozen accident,” but
rather a dynamic/developing paradigm that most
likely evolved from a “4-column code” in which Gly,
Ala, Asp, and Val were the earliest encoded amino
acids. In addition to providing “retrospective” under-
standing of the evolution and current status of the
decoding process, the new circular genetic code dia-
gram, like the periodic table of chemical elements, has
predictive power. This has the potential to aid genetic
code engineering efforts such as identification of opti-
mal codon reassignments for biosynthetic incorpo-
ration of non-canonical/non-natural amino acids,
believed to be of special interest for biotechnology
industry and for structural studies of proteins.15,16
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
I thank Drs. Henri Grosjean and Eric Westhof for useful
insights and Patricia Stanhope Baker for help with manuscript
preparation.
Funding
This work was supported by grants 13GRNT17070025 (AHA)
and HL121779-01A1 (NIH) (to A.A.K.)
References
[1] Schmeing TM, Ramakrishnan V. What recent ribosome
structures have revealed about the mechanism of transla-
tion. Nature 2009; 461:1234-42; PMID:19838167; http://
dx.doi.org/10.1038/nature08403
[2] Voorhees RM, Ramakrishnan V. Structural basis of the
translational elongation cycle. Annu Rev Biochem 2013;
82:203-36; PMID:23746255; http://dx.doi.org/10.1146/
annurev-biochem-113009-092313
[3] Melnikov S, Ben-Shem A, Garreau de Loubresse N,
Jenner L, Yusupova G, Yusupov M. One core, two shells:
bacterial and eukaryotic ribosomes. Nat Struct Mol Biol
2012; 19(6):560-7; PMID:22664983; http://dx.doi.org/
10.1038/nsmb.2313
[4] Ling J, O’Donoghue P, S€oll D. Genetic code flexibility in
microorganisms: novel mechanisms and impact on phys-
iology. Nat Rev Microbiol 2015; 13(11):707-21;
PMID:26411296; http://dx.doi.org/10.1038/nrmicro3568
[5] Bezerra AR, Guimar~aes AR, Santos MA. Non-Standard
Genetic Codes Define New Concepts for Protein Engi-
neering. Life (Basel) 2015; 5(4):1610-28;
PMID:26569314; http://dx.doi.org/10.3390/life5041610
[6] Sengupta S, Higgs PG. Pathways of Genetic Code Evolu-
tion in ancient and modern organisms. J Mol Evol 2015;
80(5–6):229-43; PMID:26054480; http://dx.doi.org/
10.1007/s00239-015-9686-8
[7] Nirenberg M, Leder P, Bernfield M, Brimacombe R,
Trupin J, Rottman F, O’Neal C. RNA codewords and pro-
tein synthesis, VII. On the general nature of the RNA code.
Proc Natl Acad Sci USA 1965; 53:1161-8; PMID:5330357
[8] Crick FH. The origin of the genetic code. J Mol Biol 1968;
38:367-79; PMID:4887876
[9] Woese CR, Dugre DH, Saxinger WC, Dugre SA. The
molecular basis for the genetic code. Proc Natl Acad Sci
USA 1966; 55:966-74; PMID:5219702
[10] Grosjean H, Westhof E. An integrated, structure- and
energy-based view of the genetic code. Nucleic Acids Res
2016; Jul 22. pii: gkw608. [Epub ahead of print];
PMID:27448410; http://dx.doi.org/10.1093/nar/gkw608
[11] Lobanov AV, Turanov AA, Hatfield DL, Gladyshev VN.
Dual functions of codons in the genetic code. Crit Rev
Biochem Mol Biol 2010; 45(4):257-65; PMID:20446809;
http://dx.doi.org/10.3109/10409231003786094
[12] Castro-Chavez F. A tetrahedral representation of the
genetic code emphasizing aspects of symmetry. BIO-
Complexity 2012; 2:1-6; PMID:22997604; http://dx.doi.
org/10.5048/BIO-C.2012.2
[13] Lavoisier A. Traite Elementaire de Chimie, presente dans un
ordre nouveau, et d’apres des decouvertes modernes (1 ed.);
1789; A Paris: Cuchet. Libraire, rue hotel Serpente
[14] Mendelejew D. €Uber die Beziehungen der Eigenschaften
zu den Atomgewichten der Elemente. Zeitschrift f€ur
Chemie 1869; 12:405-6
[15] Nikic I, Lemke EA. Genetic code expansion enabled site-
specific dual-color protein labeling: superresolution
microscopy and beyond. Curr Opin Chem Biol 2015;
28:164-73; PMID:26302384; http://dx.doi.org/10.1016/j.
cbpa.2015.07.021
[16] Neumann-Staubitz P, Neumann H. The use of unnatural
amino acids to study and engineer protein function. Curr
Opin Struct Biol 2016; 38:119-28; PMID:27318816;
http://dx.doi.org/10.1016/j.sbi.2016.06.006
e1234431-4 A. A. KOMAR