Amino Acid Modified RNA Bases as Building Blocks of an Early Earth RNA-Peptide World

Article abstract of DOI:10.1002/chem.202002929

Fossils of extinct species allow us to reconstruct the process of Darwinian evolution that led to the species diversity we see on Earth today. The origin of the first functional molecules able to undergo molecular evolution and thus eventually able to create life, are largely unknown. The most prominent idea in the field posits that biology was preceded by an era of molecular evolution, in which RNA molecules encoded information and catalysed their own replication. This RNA world concept stands against other hypotheses, that argue for example that life may have begun with catalytic peptides and primitive metabolic cycles. The question whether RNA or peptides were first is addressed by the RNA-peptide world concept, which postulates a parallel existence of both molecular species. A plausible experimental model of how such an RNA-peptide world may have looked like, however, is absent. Here we report the synthesis and physicochemical evaluation of amino acid containing adenosine bases, which are closely related to molecules that are found today in the anticodon stem-loop of tRNAs from all three kingdoms of life. We show that these adenosines lose their base pairing properties, which allow them to equip RNA with amino acids independent of the sequence context. As such we may consider them to be living molecular fossils of an extinct molecular RNA-peptide world.

Full text of DOI:10.1002/chem.202002929

Accepted Article
Accepted Article
Title: Title Amino Acid Modified RNA Bases as Building Blocks of an
Early Earth RNA-Peptide World
Authors: Thomas Carell, Milda Nainytė, Felix Müller, Giacomo
Ganazzoli, Chun-Yin Chan, Antony Crisp, and Daniel
Globisch
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002929
Link to VoR: https://doi.org/10.1002/chem.202002929
01/2020

10.1002/chem.202002929
Chemistry - A European Journal
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Title Amino Acid Modified RNA Bases as Building Blocks of an
Early Earth RNA-Peptide World
Milda Nainytė,[a] Felix Müller,[a] Giacomo Ganazzoli,[a] Chun-Yin Chan,[a] Antony Crisp,[a] Daniel
Globisch,[b] and Thomas Carell*[a]
Fossils of extinct species allow us to reconstruct the process of
Darwinian evolution that led to the species diversity we see on Earth
today. The origin of the first functional molecules able to undergo
molecular evolution and thus eventually able to create live, are largely
unknown. The most prominent idea in the field posits that biology was
preceded by an era of molecular evolution, in which RNA molecules
encoded information and catalyzed their own replication. This RNA
world concept stands against other hypotheses, that argue for
example that life may have begun with catalytic peptides and primitive
metabolic cycles. The question whether RNA or peptides were first is
addressed by the RNA-peptide world concept, which postulates a
parallel existence of both molecular species. A plausible experimental
model of how such an RNA-peptide world may have looked like,
however, is absent. Here we report the synthesis and
physicochemical evaluation of amino acid containing adenosine
bases, which are closely related to molecules that are found today in
the anticodon stem-loop of tRNAs from all three kingdoms of life. We
show that these adenosines lose their base pairing properties, which
allows them to equip RNA with amino acids independent of the
sequence context. As such we may consider them to be living
molecular fossils of an extinct molecular RNA-peptide world.
a urea connector to the N6-amino group of the heterocycle as
depicted in Fig. 1a. Particularly ubiquitous are adenosine
modifications containing the amino acids threonine (t6A)[5-7] and
glycine (g6A),[8] together with hn6A.[9,10] Based upon recent
phylogenetic analyses and the fact that t6A is found in all three
kingdoms of life, it has been suggested that such amino acid
modified bases were already present in the last universal common
ancestor (LUCA), from which all life forms descended.[11-14] t6A is
for example today found in nearly all ANN decoding tRNAs.[15] We
recently reported a plausible prebiotic route to some of these
amino acid modified A-bases, which strengthens the idea that
they could indeed be living chemical fossils of the extinct RNA-
peptide world.[16] Despite the interesting philosophical genotype-
phenotype dualism that characterizes these structures and their
contemporary importance for the faithful decoding of genetic
information, a general synthesis of aa6A modified bases (Fig. 1a)
and a systematic study of their properties is lacking.
OH
(t6A)
a)
R
H
Thr6A: R =
Ser6A: R =
Gly6A: R =
Val6A: R =
(g6A)
O
O
N
HN
OH
H
OH
N
N
H
N
O
N
N
His6A: R =
Asp6A: R =
O
N
OH
HO
OH
The RNA-peptide co-evolution hypothesis describes the
emergence of self-replicating molecules that contained amino
acids and RNA.[1] At the macromolecular level, this tight
coexistence of peptides and RNA is established in the ribosome,
where encoding and catalytic RNA is supported by proteins.[2]
Although we cannot delineate how such an early RNA-peptide
world may have looked like, it seems not too implausible to
assume that some of the molecular components may have
survived until today as vestiges of this extinct world.[3] tRNAs
derived from all three kingdoms of life contain a large number of
modified bases[4], and some of them are indeed modified with
amino acids.[3] The most wide spread amino acid modified bases
are adenosine nucleosides, in which the amino acid is linked via
Phe6A: R =
(D,L)
HO
b)
c)
[a]
[b]
M. Sc. Milda Nainytė, M. Sc. Felix Müller, M. Sc. Giacomo Ganazzoli,
B. Sc. Chun-Yin Chan, B. Sc. Antony Crisp, and Prof. Dr. T. Carell
Department of Chemistry, LMU München
Butenandtstr. 5-13, 81377 München
E-mail: thomas.carell@lmu.de
Homepage: www.carellgroup.de
Dr. Daniel Globisch
Department of Medicinal Chemistry, Uppsala University
Husargatan 3, 75123 Uppsala
Supporting information for this article is given via a link at the end of
the document.
Figure 1. (a) Depiction of the amino acid modified A-bases (aa6A) together
with computer visualizations that show how such bases may reside in an (b)
A-form RNA duplex and a (c) B-form DNA duplex. The sequence used for the
visualization is: 5'-CAUAUAUAUAUG-3' with A = g6A.
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Here we report the synthesis of a variety of aa6A nucleosides with
canonical amino acids (aa = Asp, Gly, His, Phe, Thr[17], Ser, Val),
their incorporation into DNA and RNA and an investigation of how
they influence the physicochemical properties of oligonucleotides.
We were particularly interested to study how they might affect the
stability of RNA and DNA. The computer visualization shows that
in A-form RNA (Fig. 1b), the amino acid part of the aa6A base
would need to reside inside the helix, shielded from the outside.
In the B-form DNA one could imagine a decoration of the major
groove with the amino acid side chains as depicted in Fig. 1c.
In the Schemes 1 and 2 we show the synthesis of the different
urea linked amino acid A-derivatives (aa6A). We first prepared the
amino acid components for the coupling to the A-nucleoside
(Scheme 1). Our starting points for Thr6A, Ser6A and Asp6A were
the free amino acids 1-3, in which we first transformed all
carboxylic acids into the p-nitrophenylethyl esters (npe, 4-6).[17]
The hydroxy groups of the Thr and Ser compounds were finally
protected as TBS-ethers to give the final products 7 and 8
(Scheme 1a). For Val, Gly and Phe we started with the Boc-
protected amino acids 9-11, which we also converted into the npe-
esters 12-14 using Mitsunobu type chemistry[18] followed by acidic
(4M HCl in dioxane) Boc-deprotection to give the amino acid
products 15-17 (Scheme 1b).[19] For His6A, we again started with
the Boc-protected amino acid 18 (Scheme 1c) and used HBTU
activation to generate the npe ester 19. Protection of the
imidazole Nt with POM-chloride followed again by Boc-
deprotection furnished the ready to couple amino acid 21.
good to excellent yields. Subsequent cleavage of the cyclic
silylether with HF•pyridine complex,[22,23] protection of the 5'-OH
group with dimethoxytritylchloride (DMTCl)[24] allowed the final
conversion of the compounds into the corresponding
phosphoramidites 46-52. Standard solid phase RNA chemistry[25-
31]
was subsequently employed to prepare RNA strands
containing the individual aa6A nucleosides stably embedded. The
standard RNA synthesis protocol did not require any adjustment.
In all cases we observed fair coupling of the aa6A
phosphoramidites and no decomposition during deprotection.
Deprotection required three steps. First, with DBU in THF at r.t.
for 2h we cleaved the npe-protecting group. Second, we
deprotected the bases and cleaved from the solid support with
aqueous NH3/MeNH. Finally, we removed the 2’-silyl group with
HF in NEt3.
0 oC, DCM
O
O
N
N
Cl
95%
O
N
O
Cl
N
22
H2N
H2N
1. 22, DCM
2.
N
N
N
N
CO2npe
R
N
N
N
N
NH2
Et3N, DCM
1. DTBS triflate
2. TBSCl
O
O
HO
O
85%
OH
OTBS
HO
O
Si
tBu
23
24
tBu
O
N
R
O
R
HN
N
N
CO2npe
a)
HN
N
NO2
N
CO2npe
H
NO2
H
N
N
N
N
N
TBSCl,
imidazole
npeOH
TsOH
Py*(HF)n
DCM
DMTCl
Py
R
npe
O
O
O
O
H2N
CO2H
O
R
HO
R
O
OTBS
Si
O
O
OTBS
HO
NH3
tBu
OTs
tBu
NH2
32: R = H3CCHOTBS, 95%
33: R = POM-N-imidazoyl, 75%
34: R = H3CCHCH3, 95%
35: R = H, 97%
36: R = CH2CO2npe, 98%
37a: R = CH2Ph (L), 80%
37b: R = CH2Ph (D), 78%
38: R = CH2OTBS, 96%
25: R = H3CCHOTBS, 91%
1: R = H3CCHOH
2: R = CH2OH
3: R = CH2CO2H
4: R = H3CCHOH, 70%
5: R = CH2OH, 75%
6: R = CH2CO2npe, 82%
7: R = H3CCHOTBS, 94%
8: R = CH2OTBS, 96%
26: R = POM-N-imidazoyl, 86%
27: R = H3CCHCH3, 78%
28: R = H, 71%
29: R = CH2CO2npe, 87%
30a: R = CH2Ph (L), 68%
30b: R = CH2Ph (D), 71%
31: R = CH2OTBS, 85%
b)
R
npeOH, PPh3
DIAD, DCM
R
R
HCl/Diox
H3N
Cl
CO2npe
BocHN
CO2H
BocHN
CO2npe
O
R
R
O
9: R = H3CCHCH3
10: R = H
11a: R = CH2Ph (L)
11b: R = CH2Ph (D)
12: R = H3CCHCH3, 96%
13: R = H, 85%
14a: R = CH2Ph (L), 81%
14b: R = CH2Ph (D), 85%
15: R = H3CCHCH3, 99%
16: R = H, 99%
17a: R = CH2Ph (L), 99%
17b: R = CH2Ph (D), 99%
HN
N
CO2npe
CO2npe
N
H
N
HN
H
N
Cl
O
P
N
N
CN
N
N
N
O
c)
N
O
N
POM
N
DMTO
H
N
H
N
DIPEA, DCM
O
npeOH, HBTU
O
OTBS
O
POM
N
iPr2NH, DMF
POM-Cl
N
HCl/Diox
99%
P
O
N
OTBS
DMTO
N
N
55%
93%
HO
CO2H
CO2npe
CN
N
CO2npe
BocHN
BocHN
H3N
Cl
46: R = H3CCHOTBS, 85%
47: R = POM-N-imidazoyl, 66%
48: R = H3CCHCH3, 87%
49: R = H, 86%
39: R = H3CCHOTBS, 90%
40: R = POM-N-imidazoyl, 85%
41: R = H3CCHCH3, 70%
42: R = H, 85%
19
18
CO2npe
20
21
BocHN
50: R = CH2CO2npe, 65%
51a: R = CH2Ph (L), 67%
51b: R = CH2Ph (D), 67%
52: R = CH2OTBS, 70%
43: R = CH2CO2npe, 95%
44a: R = CH2Ph (L), 82%
44b: R = CH2Ph (D), 85%
45: R = CH2OTBS, 90%
Scheme 1. Synthesis of the amino acid building blocks as needed for the
coupling to the nucleoside A to give Thr6A, Ser6A, Asp6A, Val6A, Gly6A, Phe6A
and His6A.
RNA
synthesis
[SI]
The connection of the amino acid with the A-nucleoside via the
urea moiety was next carried out as depicted in Scheme 2. We
first treated phenyl chloroformate with N-methylimidazole to
obtain the 1-N-methyl-3-phenoxycarbonyl-imidazolium chloride
(22).[20] Adenosine was converted in parallel into the cyclic 3',5'-
silyl protected nucleoside, followed by conversion of the 2'-OH
group into the TBS-ether.[21] The reaction of compound 24 with
the activated carbonate and the corresponding amino acid,
provided in all cases the amino acid coupled products 25-31 in
5’-G-U-C-X-C-C-U-G-A-3’
ON1: Thr6A; ON2: Gly6A; ON3: Val6A
ON4: His6A; ON5: Asp6A; ON6: L-Phe6A; ON7: D-Phe6A
Scheme 2. Synthesis of phosphoramidite building blocks of Thr6A, Ser6A,
Asp6A, Val6A, Gly6A, Phe6A and His6A and their incorporation into RNA.
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In order to investigate how aa6A bases would affect the stability
of DNA duplexes we also prepared as a representative molecule
t6dA as depicted in Scheme 3. To this end we first acetyl-protected
dA 53,[32] performed the coupling of the protected threonine with
the activated carbonate 22, cleaved the acetyl groups and
converted the nucleoside subsequently into the 5'-DMT protected
phosphoramidite 57. The purification of compound 57 was quite
difficult due to its high polarity. We needed to use rather polar
mixture of EtOAc/Hex (2/1) as the mobile phase for the
chromatographic separation. This provided the phosphoramidite
57, however the material had a lower purity in comparison to the
RNA phosphoramidites. Nevertheless, solid phase DNA
synthesis and deprotection of the DNA strand ODN1 proceeded
again smoothly and in high yields.
NH2
N
NH2
N
N
N
1. 22, DCM
2. 7, Et3N, DCM
3. NH3/MeOH
N
N
Ac2O
Py
N
N
O
O
80%
65%
HO
AcO
Figure 2. (a) Raw-HPL chromatogram of ON1, with the inset showing the HPL-
chromatogram of purified ON1; (b) MALDI-TOF mass spectrum of ON1 after
purification; (c) raw-HPL chromatogram of ODN1, with the inset showing the
HPL chromatogram of purified ODN1; (d) MALDI-TOF mass spectrum of ODN1
after purification.
53
HO
54
AcO
OTBS
OTBS
O
O
CO2npe
Cl
CO2npe
N
N
H
HN
H
HN
O
P
N
N
Fig. 2c and 2d show the same data set for the t6dA containing
DNA oligonucleotide (ODN1), proving again the successful
synthesis of t6dA containing oligonucleotides. The aa6(d)A
nucleosides can exist in two different conformations.[33] The first,
s-trans, maintains the Watson-Crick hydrogen bonding
capabilities with the urea amino acid oriented towards the
imidazole ring system (Fig. 3a). This allows formation of a
Hoogsteen type 7-membered ring H-bond with the N7. In the
corresponding s-cis-conformation, the urea amino acid orients
towards the Watson-Crick side thereby establishing a typically
strong intramolecular 6-membered H-bond with N1 (Fig. 3b). In
order to investigate if the embedding of the amino acid would
enforce s-trans-conformation and hence Watson-Crick H-bonding,
we measured melting points of all aa6A containing RNA strands
and of the t6dA containing DNA strand hybridized to the
corresponding counter strands (Fig. 3). In the RNA:RNA situation
we noted for all aa6A strands that we investigated, a single clear
melting point, showing that only one conformer of the aa6A base
likely exists in the RNA:RNA duplexes. In situation where the aa6A
base exists in two different stable conformations, one would
expect a more complex melting behaviour. In all cases we saw
that the melting point is strongly reduced by 10-15°C. When we
embedded two aa6A building blocks into a short RNA strands no
duplex formation was obtained. Even stronger reduction of the
melting point was observed for the DNA duplex containing one
t6dA. Here, we also saw just one sharp melting point and a
reduction of the Tm by over 20°C. These data show that the aa6A
bases and among them t6A and g6A are unable to base pair.
Although we have no direct proof of the structure the data argue
for a preferred s-cis-conformation (Fig. 3b) in agreement with the
literature.[34]
N
N
CN
N
N
N
N
N
DMTCl
Py
DIPEA, DCM
62%
O
O
72%
HO
DMTO
55
HO
56
HO
OTBS
O
OH
O
HN
N
O
N
CO2npe
H
N
N
HN
N
N
N
H
N
N
OH
N
O
DNA
synthesis
DMTO
O
O
N
5’-G-T-C-
O
P
O
O
C-C-T-G-A-3’
ODN1
CN
57
Scheme 3. Synthesis of t6dA phosphoramidite and its incorporation into DNA.
Fig. 2a shows as an example the raw HPL-chromatograms of
ON1 (RNA strand with embedded t6A) and the corresponding
chromatogram after purification (inset) together with the obtained
MALDI-TOF mass spectrum (Fig. 2b). The chromatograms of the
raw material show a good quality of the obtained RNA material.
The analytical chromatogram after purification and the MALDI-
TOF data prove the purity of the finally obtained RNA
oligonucleotide and the integrity of the t6A-containing RNA strand.
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Figure 4. (a) Depiction of the RNA structures containing aa6A nucleobases in
extrahelical positions forming either three little bulges or assembling a Ser-Asp-
His triad known as the catalytic triad in serine proteases; (b), (c) depiction of
melting curves of duplexes D5, D6, D7; S – serine, D – aspartate, H – histidine.
The melting data show, that aa6A bases alone are unable to
establish base pairing, which hinder them to encode sequence
information. On the other side, these bases allow the
incorporation of amino acids into RNA structures irrespective of
the counterbase. Because RNAs are mostly stably folded
structures in which many bases are not involved in any base
pairing or establish no Watson-Crick interactions the amino acid
adenosine nucleosides allow the stable incorporation of amino
acid functionality into RNA.
Figure 3. (a), (b) Possible conformation, base pairing and intramolecular H-
bond of aa6A; (c), (d) melting curves measured for t6A containing RNA:RNA
duplexes and of a t6dA containing DNA:DNA duplex in comparison with the
duplexes containing canonical (d)A:(d)T base pairs; (e) table of the determined
melting points.
In summary, here we investigated the synthesis and properties of
aa6A nucleoside-amino acid conjugates, some of which (t6A, g6A,
hn6A) are today found as key components in the tRNAs of many
species. In these tRNAs the aa6A nucleosides reside at the
general purine position 37 adjacent to the anticodon loop. They
are not involved in base pairing but fine tune the codon anticodon
interaction to enable faithful translation of information into a
peptide sequence.[36] Here we show that these bases are indeed
unable to base pair. They have to be placed outside the pairing
regime that is needed for RNA folding. As such they function as
anchors that allow the connection of amino acid to RNA structures
independent of the counterbase. The side chains are then
available to equip RNA with additional functions that might have
been beneficial in an early RNA-peptide world. The fact that aa6A
nucleosides are stable structures and until today broadly found in
today’s RNA make them prime candidates to develop idea about
the chemical constitution of the vanished RNA-peptide world.
This conclusion is also supported by the observation that
irrespective of the chirality of the attached amino acid (L- versus
D-Phe6A), we measured the same melting temperature. This
would not be expected if the s-trans-conformation and base
pairing would be possible. These data suggest that aa6A
nucleosides within RNA position a given amino acid outside the
A-form helix in an unpaired situation and hence independent from
the counterbase. As such, multiple aa6A containing RNA strands
would be structures in which the RNA part is decorated by the
amino acid side chains. In order to show that RNA-structures
containing multiple amino acids as representatives of an RNA-
peptide world can stably form, we prepared two RNA duplexes
(Fig. 4). In the first (D5), we placed three t6A bases as extra bases
in an otherwise undisturbed RNA duplex. Indeed, now the stability
of this duplex was indistinguishable from the same construct
containing just canonical bases (D6). Finally, we prepared an
RNA duplex D7, in which we placed the amino acids Ser-Asp-His
directly next to each other to simulate what is known in the peptide
world as the catalytic triad present in serine peptidases.[35] Again
in this case a stable duplex structure forms with the three aa6A
bases creating a loop. Although we do not show any catalytic
activity here, we believe that it is easily imaginable that if these
amino acids are properly positioned in a stably folded RNA the
structure could gain catalytic properties.
Acknowledgement:
We
thank
the
Deutsche
Forschungsgemeinschaft for financial support via SFB1309
(325871075) and SPP1784 (255344185). This project has
received funding from the European Research Council (ERC)
under the European Union's Horizon 2020 research and
innovation programme (grant agreement n° EPiR 741912) and
through a H2020 Marie Skłodowska-Curie Action (LightDyNAmics,
765866). We thank Dr. Tynchtyk Amatov for the initial synthesis
of the t6A-phosphoramidite. We thank Dr. Markus Müller for
helpful discussions and preparing Fig. 1.
Keywords: prebiotic chemistry • origin of life • RNA world •
RNA-peptide world • amino acid nucleosides
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10.1002/chem.202002929
Chemistry - A European Journal
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Naturally occurring amino acid containing nucleobases could be vestiges of an extinct early earth RNA-peptide world. Today they
help to translate genetic information, but in the RNA-peptide world, they might have been the units that equipped RNA with broad
catalytic functions. These genotype-phenotype bridging nucleosides were synthesized and their properties were investigated. We
show that these nucleosides do not base pair, which allows them to position amino acids in unpaired parts of complex RNA
structures.
6
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