Regulating Transition-Metal Catalysis through Interference by Short RNAs

Article abstract of DOI:10.1002/anie.201905333

Herein we report the discovery of a Au^I–DNA hybrid catalyst that is compatible with biological media and whose reactivity can be regulated by small complementary nucleic acid sequences. The development of this catalytic system was enabled by the discovery of a novel Au^I-mediated base pair. We found that Au^I binds DNA containing C-T mismatches. In the Au^I–DNA catalyst's latent state, the Au^I ion is sequestered by the mismatch such that it is coordinatively saturated, rendering it catalytically inactive. Upon addition of an RNA or DNA strand that is complementary to the latent catalyst's oligonucleotide backbone, catalytic activity is induced, leading to a sevenfold increase in the formation of a fluorescent product, forged through a Au^I-catalyzed hydroamination reaction. Further development of this catalytic system will expand not only the chemical space available to synthetic biological systems but also allow for temporal and spatial control of transition-metal catalysis through gene transcription.

Full text of DOI:10.1002/anie.201905333

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Accepted Article
Title: Regulating transition metal catalysis through interference by short
RNAs
Authors: Sydnee A Green, Hayden R Montgomery, Tyler R Benton,
Neil J Chan, and Hosea M. Nelson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201905333
Angew. Chem. 10.1002/ange.201905333
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10.1002/anie.201905333
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COMMUNICATION
Regulating transition metal catalysis through interference by
short RNAs
Sydnee A. Green, Hayden R. Montgomery, Tyler R. Benton, Neil J. Chan and Hosea M. Nelson*[a]
18]
sequence-selective manner,[17,
our group recently became
Abstract: Here we report the discovery of a Au(I)-DNA hybrid
catalyst that is compatible with biological media and whose reactivity
can be regulated by small complementary nucleic acid sequences.
The development of this catalytic system was enabled by the
discovery of a novel Au(I) metal-mediated base pair. We find that
Au(I) binds DNA containing C–T mismatches. In the Au(I)-DNA
catalyst’s latent state, the Au(I) ion is sequestered by the mismatch
such that it is coordinatively saturated, rendering it catalytically
inactive. Upon addition of an RNA or DNA strand that is
complementary to the latent catalyst’s oligonucleotide backbone,
catalytic activity is induced leading to a 7-fold increase in formation
interested in the development of biocatalytic systems composed
of nucleic acids and transition metals that mediate chemical
reactions.
Here, we envisioned the application of metal-
mediated base pairs[19] (MMBPs) comprised of catalytically
relevant transition metal centers and duplex DNA composed
exclusively of canonical nucleobases. Specifically, toehold-stem-
loop oligonucleotide hairpins could be designed with MMBPs
such that the metal reactivity would be regulated through outer
sphere, sense/antisense interactions with small RNA/DNA. Here,
strand displacement reactions would dictate the coordination
sphere of the reactive metal center and influence substrate
of
a
fluorescent product, forged through
a
Au(I)-catalyzed
hydroamination reaction. Further development of this catalytic
system will expand not only the chemical space available to
synthetic biological systems but also allow for temporal and spatial
control of transition metal catalysis through gene transcription
binding events (Figure 1).
In this scenario, chemical
transformations mediated by transition metal species could then
be “controlled” by inherently biological molecules. The
successful demonstration of this concept could open the door to
genotype-specific transition metal catalysis and the development
of new biosynthetic pathways that feature transformations with
no biological equivalent. Here we report the initial steps toward
achieving this goal. We find that an unprecedented Au(I) MMBP
is formed through the treatment of DNA hairpins possessing a
C–T mismatch with an appropriate Au(I) precursor. Importantly,
the rate at which this complex mediates an abiotic
hydroamination reaction is dramatically increased when exposed
to short strands of sequence-complementary DNA or RNA. This
study represents an early example of a transition metal catalyst
that can be regulated by biological stimuli.
The use of biocatalysis in synthetic chemistry is
emerging as a powerful strategy for the construction of complex
3]
molecules.[1] Protein enzymes, utilized in isolated form,[2, as
part of constructed artificial pathways,[4, 5] or encapsulated within
7]
cells programmed to express them,[6,
often form reaction
products efficiently and stereoselectively under mild conditions.
While many of the recently developed biocatalytic
transformations are mechanistically similar to native biochemical
processes, several reported systems feature distinctly abiotic
transformations, where the products of the reactions arise
through a mechanism hitherto unknown in biology. Examples
include Ru-catalyzed olefin metathesis reactions in the artificial
active site of an evolved streptavidin protein[8] and Ir- and Fe-
catalyzed metal-carbenoid and nitrenoid insertion reactions from
evolved P450 enzymes.[9] In these systems, abiotic chemical
reactivity is developed through directed evolution,[10] construction
In our initial formulation, we envisioned the design of
structured oligonucleotides that possess a sequence specific,
transition metal-binding motif (Figure 1a and 1b). While several
transition metal species are known to complex both DNA and
RNA through intrastrand or interstrand binding modes, the
catalytic activity of these species has been sparsely investigated.
This is likely due to the lack of studies concerning catalytically
relevant metals. For example, Cisplatin, the privileged anti-
cancer Pt(II) complex, binds intrastrand DNA between G–G and
G–A bases.[20] Barton and coworkers have shown that
coordinatively-saturated Ru(II) and Rh(III) complexes intercalate
dsDNA at mismatches and abasic sites.[21] Despite these
advances, there exists few examples of transition-metal-bound
DNA complexes involved in catalysis.[22] Moreover, Ag(I) ions
are known to selectively form metal-mediated base pairs
between C–C[23] mismatches, as well as Hg(II) between T–T and
C–T mismatches[24, 25]. Here, metal ion binding between the
canonical bases (C and T) leads to the formation of base-metal
bonds that are energetically similar to hydrogen bonding of
matched nucleobases, thus increasing the thermal stability of
dsDNA containing mismatches by 2–9 °C.[26]
of novel metalloenzymes via transmetallation reactions,[11]
a
posttranslational metallation,[12] or some combination thereof.[13]
It is doubtless that as these strategies improve, the availability of
protein enzymes that catalyze novel abiotic transformations will
advance in unison. However, chemical concepts allowing for
control of biocatalytic reactions by biological stimuli, a goal that
would lead to advances in synthetic biology and chemical
biology, have yet to be explored fully.[14, 15]
Inspired by current hypotheses concerning the role of
ribozymes in biogenesis,[16] the stimuli-responsiveness of
riboswitches and molecular beacons, and the well-established
propensity of late transition metals to bind nucleic acids in a
[a]
S. A. Green, H. R. Montgomery, T. R. Benton, N. J. Chan, Dr. H. M.
Nelson
Department of Chemistry and Biochemistry, University of California,
Los Angeles, Los Angeles, CA, 90095, USA.
E-mail: hosea@chem.ucla.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201905333
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a) Metal activation controlled through hybridization
possessing a C–T mismatch showed a significant increase in
thermal stability (Tm) when exposed to one equivalent of
(Me2S)AuCl (Figure 1c), with no apparent formation of Au-
nanoparticles. Moreover, titration experiments indicated the
incorporation of a single gold ion into the dsDNA (Figure 1c).
We note that the thermal stability melting curves are slightly
biphasic, likely due to incomplete metal-medaited base pair
formation or weak binding at neutral pH (SI, Figure S4 and S5).
Circular dichroism (CD) experiments support preserved helicity
upon exposure to (Me2S)AuCl, suggesting that Au(I) binding
does not interrupt helicity or cause appreciable changes in the
overall secondary structure.[35] (SI, Figure S6 and S7). Mass
spectrometry studies also support incorporation of a single Au(I)
ion, as the base peak of recorded spectra coincided with the
mass of the addition of one gold ion. Importantly, in control
studies utilizing a 14-mer containing no mismatch, there was
minimal Au-adducts observed (SI, Figure S9).
M
M
hybridization to small
interfering sequence
1
2
b) Gold MMBP within a Thymine–Cytosine mismatch
H
H
O
H
N
(Me2S)AuCl
(1 equiv)
O
H
N
AuI
N
H
N
N
N
H2O:MeOH
(60:1 v/v)
N
N
N
N
O
O
O
O
R
R
R
R
T—C mismatch
Au mediated T—C base pair
3
c) UV thermal stability titration of C–T mismatch
0 equiv Au(I)
1.0
a) Gold(I) catalyst preparation
0.4 equiv Au(I)
50
1 equiv Au(I)
1.4 equiv Au(I)
2 equiv Au(I)
3 equiv Au(I)
5’ CGTTCTG
5’ CGTTCTG
(Me2S)AuCl
T(4)
T(4)
= AuI
incorporation
3’ CTACAGCACGAC
3’ CTACAGCACGAC
45
40
0.5
0.0
4
5
masked Au(I) precatalyst
toehold C–T mismatch
3’ CAAAAGTCGTGCTGTAG 5’
strand displacement
0
1
2
3
20
40
60
80
Equivalents of Au(I)
Temperature (°C)
profluorescent starting
material
Figure 1. a) Proposed formation of active catalyst from DNA-metal complex.
b) Putative binding of Au(I) into C–T mismatch. c) UV melting curve of duplex
CT1 (5’ – CCT TTC TTT CCC TC – 3’ • 5’ – GAG GGA CAG AAA GG – 3’)
with varying amounts of (Me2S)AuCl at pH 7.
5’ CGTTCTGTTTTCAGCACGACATC 3’
CAAAAGTCGTGCTGTAG 5’
6
catalytically active Au(I)
fluorescent product
b) Gold(I)-catalyzed hydroamination
The reported Ag- and Hg-mediated base pairs inspired
us to consider the construction of a Au-mediated base pair, as
OMe
Au(I) shares
a similar preference for linear coordination
N
H2N
geometries. Additionally, in bioactive Au(I) complexes,
interactions between the gold center and DNA have been
implicated as modes of action towards disease treatment.[27–28]
Interestingly, the potential for interstrand binding of Au(I) to
dsDNA was originally proposed over three decades ago by
Blank and Dabrowiak.[29] Spectroscopic experiments support the
binding of Au(III) and Au(I) to the N7 of guanine and also
support the formation of a dimeric Au(II) complex between two
cytosine nucleosides.[30] In addition, there is crystallographic
evidence of Au(III) binding to a C–G pair in HIV-1 RNA.[31]
Despite this evidence, several early reports attempting a Au(I)–
MMBP utilizing simple AuCl and AuCl3 salts were unsucessful.[32,
[Au]
OMe
hydroamination
EtO2C
CO2Et
EtO2C
CO2Et
N
N
N
N
B
8
B
7
F
F
F
F
c) Fluorescence of (8) in response to latent complex (5) and active complex (6).
Conditions
40000
5
6
30000
20000
10000
0
33]
In our hands, use of these inorganic salts led to the rapid
formation of purple precipitates (presumably Au-nanoparticles)
when exposed to dsDNA bearing a C–T mismatch and we noted
no increase in thermal stability (SI, Figure S3).
+
–
5
6
Conditions
Figure 3. a) Proposed incorporation of Au(I) into DNA hairpin followed by
hybridization to expose coordination site on the metal center. b)
a
Profluorescent BODIPY cyclization catalyzed by addition of DNA-Au complex.
c) Fluorescence intensity of reactions containing Au(I) only (+), no Au(I) or
DNA (-), latent complex 5, and active complex 6 on left graph. Image: latent
complex 5 with fluorophore on left and active complex 6 with profluorophore
on right.
Informed by the homogeneous transition metal
catalysis community, we examined different Au(I) precursors.[34]
We were gratified to find that thermal stability analysis of a 14-
mer dsDNA and an 18-mer hairpin sequence (SI, Figure S2)
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a) Hairpin containing G–C
(GCH5) instead of T–C (TCH5)
b) Fluorescence fold increase with
different mismatched complements
Having successfully created a sequence-specific transition
metal binding motif through formation of a Au(I)-mediated base
pair, we moved forward with investigations of its catalytic
properties. We hypothesized that the hairpin containing a C–T
mismatch in the stem (4) would bind one equivalent of Au(I) to
form latent DNA-Au complex 5 (Figure 3a). Upon exposure to a
short, complementary DNA or RNA sequence, strand
displacement would interfere with the Au–base bonds of the
stable MMBP, forming an active complex 6. We assessed the
catalytic activity of this complex using pro-fluorophore 7, which
cyclizes to form fluorescent BODIPY 8 through a Au-catalyzed
hydroamination reaction, allowing for high throughput sequence
optimization using a simple plate reader (Figure 3b).
8
6
4
2
0
10
8
6
4
2
0
TCHX5
GCHX5
1
comp
R
TMd 5d
3d TMs 3s
5s
1
Conditions
Sequence
c) Increase in fluorescence in response to mismatched complement
sequences
3’ CTA CAG CAC GAC TTT TGT CTT GC 5’
Name
cCTH5
R1
Sequence
Fold Increase
5’ GAT GTC GTG CTG AAA AC 3’
6.5 ± 0.9
0.5 ± 0.2
2.0 ± 0.4
3.2 ± 0.2
3.5 ± 0.7
2.2 ± 0.7
3.5 ± 0.5
4.3 ± 0.9
We were pleased to find that treatment of latent DNA-
Au catalyst 5 with 1 equivalent of a complementary short
oligonucleotide sequence (cCTH5) increases the fluorescence
of a solution containing pro-fluorophore 7 by approximately 7-
fold (Figure 3c). To further support that observed reactivity was
due to the modulation of the Au(I)-mediated base pair in a
sequence-specific manner, we carried out further control
experiments. First, it was necessary to confirm that the formation
of latent complex 5 is dependent on the presence of a C–T
mismatch. Exposure of a solution of (Me2S)AuCl and a hairpin
containing no DNA mismatches (a G–C base pair instead of a
C–T mismatch in complex (5)) to the complement strand
(cCTH5) did not result in an increase of fluorescence (Figure
4a). This suggests that the formation of a precatalytic complex,
such as complex 5, is dependent on the presence of a mismatch.
Moreover, when the complementary strand (cCTH5) was
replaced with non-complementary, purine-rich, random DNA
sequence R1, the latent DNA-Au catalyst 5 is not significantly
activated, as minimal increase in fluorescence is observed
(Figure 4b and 4c). In sequence-selectivity experiments, the
highest increase in fluorescence is exhibited in the presence of
the exact complementary sequence (cCTH5), whereas addition
of complements possessing single (1-nt) or double (2-nt)
mismatches (TMs/3s/5s and TMd/3d/5d, respectively) result in
lower fluorescence intensity, with the 2-nt mismatched sequence
TMd resulting in the lowest levels of fluorescence (Figure 4b
and 4c). Moreover, a FRET-based probe demonstrated that
strand displacement occurs even in the presence of Au(I)-
mediated base pair despite the strong Au-base bonds (SI,
Figure S14). These control experiments support our hypothesis
that complement hybridization is required to form the active
catalyst.
5’ GAG GGA TAG AAA GG
3’
TMd
5d
5’ GAG ATC GTG CTG AAA AC 3’
5’ GAT GTC GGG ATG AAA AC 3’
5’ GAT GTC GTG CTG AAA GA 3’
5’ GAT GTC GTG ATG AAA AC 3’
5’ GAT ATC GTG CTG AAA AC 3’
5’ GAT TGC GTG CTG AAA AA 3’
3d
5s
TMs
3s
e) RNA complement (RcCTH5) and
DNA complement (cCTH5)
d) Reaction under various biological
conditions
10
8
6
4
2
0
6
4
2
0
cCTH5 only
R1
Urine
Additive
Saliva
cCTH5
RcCTH5
Complement
Figure 4. a) Control experiment with hairpin sequence containing G–C match
instead of C–T mismatch (GCH5 : 5’ – CGT GCT GTT TTC AGC ACG ACA
TC – 3’). b) Fold increase in fluorecence of haiprin sequence with mismatched
complement sequences. c) Mismatch complement sequences. d)
Fluorescence intensity of complex 5 and complex 6 (Figure 3) without any
additive (5 only) and with added nucleic acids, R1, and biological fluids,
synthetic urine and synthetic saliva. e) Fold increase in yield following the
addition of RcCTH5 (5’ – GAU GUC GUG CUG AAA AC – 3’).
Biological systems contain many potential ligands for
metal binding, leading to difficulties developing biocompatible
complexes and controlling abiotic metal reactivity under
physiological conditions. Specifically, Au(I) and Au(III) have
been shown to readily form nanoparticles in the presence of
small biomolecules, such as short nucleic acids, amino acids,
and sugars.[36] To assess the stability and reactivity of complex 5
under biological conditions, we exposed our catalyst system to
mixtures of nucleic acids and to biologically relevant solutions.
We have observed that random DNA sequences, such as R1,
attenuate the conversion of fluorophore 7 by (Me2S)AuCl, likely
due to competitive binding of Au(I) by free bases (SI, S15).
Therefore, we sought to explore if our complex could still be
activated by
a
complement in the presence of non-
complementary DNA sequences, to mimic complex biological
environments which will contain extraneous nucleic acids. We
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COMMUNICATION
National Institutes of Health under instrumentation grant no.
1S10OD016387-01.
were pleased to find that the addition of a mixture of random
sequence R1 and complement cCTH5 to latent catalyst 5, led to
a 1.5-fold increase in fluorescence, a significant increase in
reactivity when compared to complex 5 alone (Figure 4d). In
addition, complex 6 showed significant catalytic activity in
solutions of urine or saliva, with nearly a 2-fold and 4-fold
increase in yield, respectively. This result is especially
remarkable due to the fact that these solutions contain albumin,
an enzyme with a considerable amount of sulfur containing
residues,[37] and urea, a small molecule well known to denature
DNA.[38]
Keywords: DNAzyme • metal-mediated base pair • Au(I)-
catalyzed hydroamination • biocatalysis
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Financial support was generously provided by the Packard
Foundation and Pew Charitable Trusts (to H. M. N.). The
authors thank Prof. F. Dean Toste (UC Berkeley) for inspiration.
We also thank Dr. Jeff Vieregg (University of Chicago) for useful
discussions. The authors thank the UCLA Molecular
Instrumentation Center for NMR instrumentation and Mass
Spectrometry. This material is based on work supported by the
M.
Arachchilage,
S.
Basu,
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2016,
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Entry for the Table of Contents (Please choose one layout)
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Sydnee A. Green, Hayden R.
Montgomery, Tyler R. Benton, Neil J.
Chan, and Hosea M. Nelson*
Page No. – Page No.
Regulating transition metal catalysis
through interference by short RNAs
Good as gold: A DNA hairpin containing a C–T mismatch complexes with Au(I), forming a
novel MMPB and inhibiting the catalytic activity of the Au species. Upon the addition of the
complement strand, Au(I) is poised to catalyze a hydroamination on a pro-fluorescent BODIPY
substrate. This system presents excellent complement sequence specificity, even when
challenged with extraneous biological material, forging an early example of abiotic transition
metal catalysis controlled by genetic information.
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