Semi-Rationally Designed Short Peptides Self-Assemble and Bind Hemin to Promote Cyclopropanation

Article abstract of DOI:10.1002/anie.201916712

The self-assembly of short peptides gives rise to versatile nanoassemblies capable of promoting efficient catalysis. We have semi-rationally designed a series of seven-residue peptides that form hemin-binding catalytic amyloids to facilitate enantioselect

Full text of DOI:10.1002/anie.201916712

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Accepted Article
Title: Semi-Rationally Designed Short Peptides Self-Assemble and
Bind Hemin to Promote Cyclopropanation
Authors: Ivan Korendovych and Oleksii Zozulia
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916712
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Semi-Rationally Designed Short Peptides Self-Assemble and Bind
Hemin to Promote Cyclopropanation
Oleksii Zozulia and Ivan V. Korendovych*[a]
Abstract: Self-assembly of short peptides gives rise to versatile
nanoassemblies capable of promoting efficient catalysis. We have
semi-rationally designed a series of seven-residue peptides that form
hemin-binding catalytic amyloids to facilitate enantioselective
cyclopropanation with efficiencies that rival those of engineered hemin
proteins. These results demonstrate that: 1. Catalytic amyloids can
bind complex metallocofactors to promote practically important
multisubstrate transformations; 2. Even essentially flat surfaces of
major challenge in de novo designed catalytic systems as
productive association of different substrates with the active sites
is necessary for efficient turnover. Moreover, we are interested in
reactions that are bond-forming and resulting in formation of
complex products. Finally, in this work we probed whether
fundamentally chiral peptides that nonetheless form fairly flat
assemblies[4c] are capable of enantioselective catalysis. In this
study we focused on cyclopropanation of aromatic styrenes
(Scheme 1); this practically important reaction results in formation
of carbon-carbon bonds with new stereocenters.[7] Engineered
heme-containing proteins have been shown to promote this
transformation with high efficiency and enantioselectivity,[8] but
the question whether peptide assemblies can support this
transformation remained unanswered.
amyloid assemblies can impart
a
substantial degree of
enantioselectivity without the need for extensive optimization; 3. The
ease of peptide preparation allows for straightforward incorporation of
unnatural amino acids and preparation of peptides made of D-amino
acids with complete reversal of enantioselectivity.
Self-assembly is
a
powerful tool to create large
supramolecular structures with a wide range of practically
important applications ranging from biomineralization to
catalysis.[1] Peptides, having functional groups that provide
hydrogen bonding, electrostatic interactions, aromatic stacking
and van der Waals forces, are particularly well suited to serve as
building blocks for larger supramolecular structures.[2] Recently,
discovery of highly efficient and functionally versatile catalytic
amyloids showed great potential for development of new, easy to
make, stable and robust catalysts, for a variety of chemical
transformations.[3]
Scheme 1. Schematic representation of hemin association with catalytic
Catalytic amyloids show catalytic efficiency that rival those
of natural enzymes by weight[4] and can facilitate hydrolytic and
redox transformations as well as tandem reactions.[5] At the same
time none of the successful examples of catalytic amyloids
reported have yet to tap into the incredible potential of complex
metal-containing cofactors. Porphyrin derivatives are widely used
in nature for a diverse set of applications ranging from light
harvesting to respiration and C-H bond activation, thus we
decided to explore the potential of self-assembling peptides to
accommodate hemin in a functional manner. Despite the
outstanding potential of the porphyrin-based cofactors to promote
catalysis examples of its use in self-assembled peptide systems
remain sparse and are limited to peroxidase activity.[3i, 6]
amyloids to promote cyclopropanation.
Previously we have developed a series of seven-residue
peptides capable of self-assembly in the presence of transition
metal ions to form catalytic amyloids that promote hydrolytic and
redox transformations.[4a, 4b, 5] First, we have tested the ability of
these peptides to coordinate hemin. The Soret band offers a
sensitive and informative tool for quantitative characterization of
association of various metalloporphyrins with exogenous ligands.
Interestingly, the peptides that showed the highest propensity to
promote hydrolysis in the presence of Zn2+ (Ac-IHIHIQI-CONH2
and Ac-IHIHIYI-CONH2) did not show any appreciable binding of
hemin (Figure S1j-k, Supporting Information). Similarly, the valine
core peptides that assemble rapidly both in the presence and
absence of transition metals did not associate with hemin. At the
same time, a distinct shift in Soret band was observed after 24
hours of incubation of hemin at pH 7 with Ac-LHLHLQL-NH2
(Figure S1l, Supporting Information), a peptide that relies of the
leucine core for self-assembly with morphology different from that
of Ac-IHIHIQI-CONH2, indicating some degree of histidine-iron
coordination.
Here we set out to explore whether catalytic amyloids can
effectively bind hemin to efficiently promote catalysis in
multisubstrate reactions. Multisubstrate reactions constitute a
[a]
Dr. Oleksii Zozulia, Prof. Dr. Ivan V. Korendovych
Department of Chemistry, Syracuse University
111 College Place, Syracuse, NY 13244 (USA)
E-mail: ikorendo@syr.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under
http://dx.doi.org/10.1002/anie.201602480
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10.1002/anie.201916712
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the chiral environment around the porphyrin ring (Figure 1B,
Inset).[9]
Excitingly, the resulting assemblies are capable of
promoting diastereo- and enantiospecific cyclopropanation, albeit
with modest yields and selectivities (Table 1). The diasteromeric
ratio is fairly similar (within 10%) to the values shown by the hemin
alone consistent with the overall reaction mechanism.
In the next round of the design we focused on the residues
responsible for metal coordination. Since only one histidine
residue is required for hemin coordination, next we determined
which one is best suited for functional incorporation of hemin into
fibrils. We prepared two peptides where either of the histidine was
replaced with alanine (Ac-LALHLFL-NH2 and Ac-LHLALFL-NH2)
and spectroscopically monitored their association with hemin
(Figure S1a-b, Supporting Information). Both peptides bound
hemin, but the Soret band red shift is slightly more pronounced in
the former case.
Both peptides promoted cyclopropanation of 4-
(trifluoromethyl)styrene with ethyl diazoacetate (EDA).
Importantly, Ac-LALHLFL-NH2-hemin showed enantioselectivity
favoring the cis-1S,2R and 3% trans-1S,2S products (Table 1).
Having identified that the binding of hemin by histidine in the
fourth position is important for enantioselectivity, we subsequently
probed the effect of different residues in position 2. In agreement
with our original findings we observed that introduction of
hydrophobic moieties further improved binding and reactivity of
the self-assembling catalysts, whereas our attempts to introduce
hydrogen bond donors did not produce any improvement in
yields/selectivity of cyclopropanation reactions (Table 1).
Considering that all peptides bound hemin and formed β-sheet
assemblies (Figures S1, S5, S6, Supporting Information) this
observation suggests that minor changes in sequence result in
substantial changes in reactivity.
Table 1. Catalytic activity and selectivity of peptide-hemin complexes in
cyclopropanation of 4-(trifluoromethyl)styrene with EDA.[a]
Peptide
Yield, %[b]
39
de, % [c]
76
eecis, %[d]
eetrans, %[d]
Figure 1. (A) UV-Vis spectra of 4 μM hemin (dotted trace), mixture of 30 μM Ac-
LHLHLFL-NH2 with 4 μM hemin (dashed trace) and 30 μM Ac-LILHLFL-NH2 with
4 μM hemin (solid trace). Inset: EPR spectrum of 750 μM Ac-LILHLFL-NH2 with
100 μM hemin (B) Circular Dichroism spectra of 30 μM Ac-LHLHLFL-NH2
(dashed trace) and 30 μM Ac-LILHLFL-NH2 (solid trace). Inset: CD of Soret
band of LHLHLFL-NH2 with 4 μM hemin (dashed trace) and 30 μM Ac-LILHLFL-
NH2 with 4 μM hemin (solid trace). All measurements were taken in 100 mM
phosphate buffer at pH 7 after 24 hours of incubation.
LHLHLFL
LHLALFL
LALHLFL
LFLHLFL
4
6
22
81
4
3
28
69
6
7
42
77
<1
1
<1
6
LLLHLFL
48
72
Encouraged by this result, we investigated the role of polar
residues in position 6 of the sequence on hemin binding
properties. Specifically, we replaced Gln to Phe to achieve two
goals: a) increase hydrophobicity of the assembly thus making it
more likely to interact with both hydrophobic cofactor and,
ultimately, hydrophobic substrates; b) favor hemin binding to
fibrils by introducing stacking interactions between the aromatic
system of the cofactor and the side chain of the newly introduced
amino acid. The resulting peptide Ac-LHLHLFL-NH2 forms β-
sheet assemblies (Figure 1B) which bind hemin as shown by a
significant (more than 20 nm) red shift of the Soret band maximum
to 422 nm after 24 hours of incubation (Figure 1A) and the
emergence of the corresponding bifurcated CD signal confirming
LTLHLFL
30
72
0
1
LILHLFL
52
68
-12
9
40
5
LGLHLFL
LVLHLFL
LMLHLFL
LHLH(L-NMe)FL
LIL(3Me-H)LFL
AHAHAFA
31
66
16
75
5
25
16
0
26
65
5
16
80
0
18
77
0
0
71
77
0
<1
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10.1002/anie.201916712
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analog Ac-AHAHAFA-NH2 demonstrated improvement in activity,
in fact it was the most active peptide of the series, yet showed no
enantioselectivity. These results have two important implications:
axial hemin coordination with a concomitant breakup of hemin
aggregates leads to a large improvement in ability of the cofactor
to promote cyclopropanation and self-assembly to create higher
order supramolecular structures is absolutely essential for the
enantioselectivity of the resulting catalysts.
Hemin
15
70
0
0
[a] Reaction conditions: 20 μM hemin with 150 μM peptide, 8 mM styrene, 24
mM EDA, 10 mM sodium dithionite, 100 mM phosphate buffer pH 7, 1 h. The
catalysts were incubated for 24 hours prior to the experiments. [b] Yields were
determined using GC. [c] Diastereomeric excess (de) values were calculated
using the formula de = 100 x ([trans] – [cis])/([trans] + [cis]) [d] Enantiomeric
excess (ee) values were calculated using the formulae: eecis = 100 x ([1S,2R] –
[1R,2S])/([1S,2R] + [1R,2S]); eetrans = 100 x ([1S,2S] – [1R,2R])/([1S,2S] +
[1R,2R]).
Ac-LILHLFL-NH2 showed the highest enantioselectivity and
was characterized in more detail. Transmission electron
microscopy (TEM) of Ac-LILHLFL-NH2 in complex with hemin
(10:1 peptide:hemin ratio, Figure 2) shows well-resolved amyloid-
like assemblies with morphologies that are distinctly different to
those formed by Ac-LHLHLFL-NH2 (Figure S2a-b Supporting
Information). The CD spectra of the fibrils are consistent with β-
sheet secondary structure and the emergence of the CD signature
in the Soret band region demonstrates hemin association with the
catalysts (Figure 1A, B). Interestingly, the Soret band CD signal
shows a lesser degree of exciton coupling as compared to
LHLHLFL-hemin consistent with a slightly different cofactor
microenvironment. UV-Vis titration studies, including a Job plot,
of hemin association with peptide assemblies demonstrate ~4:1
peptide monomer to hemin stoichiometry (Figure S3, Supporting
Information) with an apparent Kd of 2 ± 0.7 M. The EPR studies
of the Ac-LILHLFL-NH2 – hemin complex show a typical axial high
spin Fe(III) heme signature consistent with a single histidine
coordination of the iron (Figure 1A). This observation can also
serve as indirect evidence that most of the cofactors are located
on the surface of the fibrils and are easily accessible for the
substrate.
Figure 2. Representative TEM images of nanostructures formed by Ac-
LILHLFL-NH2 with hemin (peptide:hemin is 10:1) in 100 mM pH 7 phosphate
buffer and incubated for 24 hours.
Having identified Ac-LILHLFL-NH2 as the peptide that
imparts the greatest enantioselectivity, we performed a substrate
scope studies (Table 2). In all cases tested, which included both
electron deficient and electron rich substrates, as well as
substrates with various substitution patterns we observed
cyclopropanation with good product yields (Table 2). Moreover, in
all cases the catalyst was enantioselective, albeit with a different
degree of preference for the trans-1S,2S products.
Table 2. Substrate scope in cyclopropanation reaction catalyzed by peptide-
Given the ease of incorporation of unnatural amino acids
into short peptide sequences we probed the effects of substituting
the hemin-binding histidine in Ac-LILHLFL-NH2 with 3-methyl-
histidine (3Me-H). 3Me-H has been previously shown to improve
catalytic properties in engineered myoglobins.[10] While
introduction of the unnatural amino acid did not disrupt the
assembly as confirmed by CD spectra (Figure S5n, Supporting
Information) the hemin Soret band position was significantly
different from the one in the hemin-Ac-LILHLFL-NH2 assemblies
(Figure S6f, Supporting Information). Moreover, Ac-LIL(3Me-
H)LFL-NH2-hemin complex showed no enantioselectivity in
cyclopropanation (Table 1). This observation suggests potential
importance of the hydrogen bonding in the histidine side chain for
binding of the cofactor in the catalytically competent conformation.
In order to evaluate the effects of self-assembly on peptide
reactivity and enantioselectivity we tested cyclopropanation
promoted by hemin itself as well as hemin in the complex with
peptides that do not form assemblies in the presence of the
cofactor. Hemin on its own promotes cyclopropanation quite
poorly giving a 70% de and no enantiomeric excess (Table 1). We
have also prepared Ac-LHLH(L-NMe)FL-NH2 which had
methylated backbone nitrogen, as well as a related peptide Ac-
hemin -assemblies.[a]
Substrate
styrene
Catalyst
Yiel,
%
eecis
%
,
eetrans
%
,
[b]
[c]
[c]
Ac-LILHLFL-NH2
68
70
80
74
52
50
71
88
65
61
95
91
-12
13
-13
13
-12
11
-8
19
(D)-Ac-LILHLFL-NH2
Ac-LILHLFL-NH2
-19
38
4-chlorostyrene
(D)-Ac-LILHLFL-NH2
Ac-LILHLFL-NH2
-39
40
4-(trifluoromethyl)
styrene
(D)-Ac-LILHLFL-NH2
Ac-LILHLFL-NH2
-40
26
4-vinylphenylacetate
3-methylstyrene
α-methylstyrene
(D)-Ac-LILHLFL-NH2
Ac-LILHLFL-NH2
7
-27
28
-20
19
-7
(D)-Ac-LILHLFL-NH2
Ac-LILHLFL-NH2
-26
24
AHAHAFA-NH2 that lacks
a
hydrophobic core. These
(D)-Ac-LILHLFL-NH2
7
-25
modifications render both peptides incapable of self-assembly as
well as forming secondary structures, although they still bind
hemin to some extent (Figure S1f, S6e, Supporting Information).
Ac-LHLH(L-NMe)FL-NH2 shows the activity levels comparable to
those of the uncoordinated hemin, whereas its more hydrophilic
[a] Reaction conditions: 20 μM hemin with 150 μM peptide, 8 mM styrene, 24
mM EDA, 10 mM dithionite, 100 mM pH 7 phosphate buffer, 1 h. [b] Yields were
based on GC analysis of the worked up reaction mixture. Enantiomeric excess
(ee) values were calculated using the formulae: eecis = 100 x ([1S,2R] –
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[1R,2S])/([1S,2R] + [1R,2S]); eetrans = 100 x ([1S,2S] – [1R,2R])/([1S,2S] +
[1R,2R]).
Mb
H64V/
V68A[c]
-
5
2
[11a]
We chose two representative peptides for in depth kinetic
characterization: the most enantioselective Ac-LILHLFL-NH2 as
well as the “middle of the pack” Ac-LALHLFL-NH2 capable of
binding the hemin productively, but not showing high selectivity.
Global fit of the initial rate dependence on substrate
concentrations (Figure 3, Figure S4) was in agreement with the
ping-pong two substrate kinetic model. The corresponding kinetic
parameters are given in Table 3. Comparison of the self-
assembled peptides with engineered heme proteins is instructive
(although it should be noted that the experimental conditions vary
somewhat between the studies and global fitting was not
employed for the proteins). The turnover rates shown by the short
peptides are comparable to the ones shown by heme enzymes,
consistent with the fact that the properly ligated cofactor itself is
primarily responsible for the reactivity. Interestingly, the Michaelis
constants for EDA are significantly lower for the self-assembled
system when compared to the proteins, a result that is perhaps
unexpected for a system with fairly open access to heme and that
potentially speaks to much potential in further improving
enzymatic cavity in myoglobin and cytochromes P450 for the first
step of the reaction. The Michaelis constants for styrenes are
comparable between the peptides and enzymes.
[a] Reaction conditions: 20 μM hemin with 150 μM peptide, 1 – 8 mM 4-
(trifluoromethyl)styrene, 2.5 – 24 mM EDA, 10 mM dithionite, 100 mM pH 7
phosphate buffer. [b] Reaction was performed at pH 8 with 0.2-20 mM EDA and
30 mM styrene or 0.2-15 mM styrene and 20 mM EDA [c] Reaction was
performed at pH 7 with styrene as substrate.
While the observed enantioselectivities are modest compared
to those obtained with engineered hemin proteins, short peptides
are very easy to prepare and modify. This feature allows for a
straightforward preparation of the opposite enantiomers of the
catalysts, a feat that is nearly impossible to do with proteins
limiting their use in practical applications. We prepared (D)-Ac-
LILHLFL-NH2, an enantiomer of the most selective catalysts and
tested its ability to promote enantioselective cyclopropanation
(Table 2). Excitingly, the enantioselectivities of (D)-Ac-LILHLFL-
NH2 are exactly (within the error of measurement) opposite to
those of Ac-LILHLFL-NH2 demonstrating the ease with which
catalysts with opposite enantioselectivities can be prepared whilst
and showing that the selectivity of the catalyst is fundamentally
linked to the chirality of the monomeric peptides. As expected, the
bulk morphological properties and hemin affinities of (D)-Ac-
LILHLFL-CONH2 are identifcal to those of its enantiomer (Figure
S5o, S6h Supporting Information).
In summary, while efficient and enantioselective
cyclopropanation has been considered a prerogative of complex
proteins, our studies showed for the first time that catalytic
amyloids formed by very short peptides can bind complex
metallocofactor in a highly sequence specific, functional manner
to create efficient and enantioselective catalysts of
cyclopropanation. This result was achieved by a conservative
introduction of only two changes into the sequence of a catalytic
amyloid-forming peptide incapable of binding hemin. The
efficiencies of these catalysts are comparable to some
engineered proteins[11] and demonstrate the ease with which
hemin can be employed to promote cyclopropanation in general,
at the same time the observed enantioselectivities are modest,
consistent with the lack of a well-defined enclosed catalytic site
found in globular proteins. Nonetheless, it is quite striking that
self-assembly of short peptides into essentially flat surfaces
results in any enantioselectivity at all and this observation
suggests more subtle effects of the assembly on the transition
state of the reaction. From a standpoint of Origin of Life, a rapid
emergence of enantioselective catalysis in simple assemblies that
can be formed abiotically lends credence to the “amyloids-first”
hypothesis.[12] Finally, we have shown the potential for catalytic
amyloids to promote multi-substrate reactions that require
interactions of the catalysts with substrate with different physico-
chemical properties. Together with ease of preparation and
chemical modification as well as the simplicity of stereochemistry
flipping, short self-assembling peptides demonstrate unique and
versatile catalytic properties with great potential for customization.
Figure 3. Initial rates of 4-(trifluoromethyl)styrene cyclopropanation with EDA
catalyzed by Ac-LILHLFL-NH2-hemin complex (20 μM hemin mixed with 150 μM
peptide) at pH 7 in 100 mM phosphate buffer.
Table 3. Kinetic parameters for cyclopropanation promoted by hemin-bound
self-assembled peptides and representative engineered heme proteins.
KM(Styrene),
Catalyst
kcat, s-1
KM(EDA), mM
Ref.
mM
LILHLFL -
hemin[a]
this
work
0.905 ± 0.068
2.96 ± 0.55
2.76 ± 0.42
LALHLFL-
hemin[a]
this
work
0.600 ± 0.004
1.7 ± 0.4
3.06 ± 0.45
5.2 ± 3.5
2.01 ± 0.26
1.4 ± 0.5
Acknowledgements
P450BM3-
heme-CIS[b]
[13]
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R. K. C. Yamijala, K. Tao, L. J. W. Shimon, D. S. Eisenberg, M. R.
Sawaya, B. M. Wong, E. Gazit, Nat. Catal. 2019, 2, 977-985; l) O. V.
Makhlynets, I. V. Korendovych, Nat. Catal. 2019, 2, 949-950.
a) C. M. Rufo, Y. S. Moroz, O. V. Moroz, J. Stöhr, T. A. Smith, X. Hu, W.
F. DeGrado, I. V. Korendovych, Nat. Chem. 2014, 6, 303; b) O. V.
Makhlynets, P. M. Gosavi, I. V. Korendovych, Angew. Chem. Int. Ed.
2016, 55, 9017-9020; c) M. Lee, T. Wang, O. V. Makhlynets, Y. Wu, N.
F. Polizzi, H. Wu, P. M. Gosavi, J. Stöhr, I. V. Korendovych, W. F.
DeGrado, M. Hong, Proc. Natl. Acad. Sci. U.S.A. 2017, 114, 6191-6196.
Z. Lengyel, C. M. Rufo, Y. S. Moroz, O. V. Makhlynets, I. V. Korendovych,
ACS Catal. 2018, 8, 59-62.
This work was supported by the NIH (Grants No. GM119634,
GM103521), the CRDF (Grant No. OISE-18-63891-0) and the
Alexander von Humboldt Foundation. We thank Prof. Nancy
Totah for providing access to a GC instrument. We thank Dr. Boris
Dzikovski for help with acquisition of the EPR spectra. We thank
Dr. Min Chul Kim and Ngoc T. Huynh for assistance in peptide
purification and GC analysis.
[4]
[5]
[6]
Keywords: self-assembly, peptide, amyloid, catalysis,
cyclopropanation.
a) Q. Wang, Z. Yang, M. Ma, C. K. Chang, B. Xu, Chem. Eur. J. 2008,
14, 5073-5078; b) H. Atamna, K. Boyle, Proc. Natl. Acad. Sci. U.S.A.
2006, 103, 3381-3386.
[1]
[2]
a) M. Boncheva, G. M. Whitesides, MRS Bull. 2011, 30, 736-742; b) I. W.
Hamley, Interface Focus 2017, 7, 20170062.
[7]
a) T. Hayashi, M. Tinzl, T. Mori, U. Krengel, J. Proppe, J. Soetbeer, D.
Klose, G. Jeschke, M. Reiher, D. Hilvert, Nat. Catal. 2018, 1, 578-584; b)
H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, J. Tanko, T. Hudlicky,
Chem. Rev. 1989, 89, 165-198; c) A. J. Burke, C. S. Marques, N. J.
Turner, G. J. Hermann, Active Pharmaceutical Ingredients in Synthesis:
Catalytic Processes in Research and Development, John Wiley & Sons,
2018.
a) A. C. Mendes, E. T. Baran, R. L. Reis, H. S. Azevedo, WIREs
Nanomed. Nanobi. 2013, 5, 582-612; b) I. Cherny, E. Gazit, Angew.
Chem. Int. Ed. 2008, 47, 4062-4069; c) X. Du, J. Zhou, J. Shi, B. Xu,
Chem. Rev. 2015, 115, 13165-13307; d) N. Habibi, N. Kamaly, A. Memic,
H. Shafiee, Nano Today 2016, 11, 41-60; e) A. Lupas, Trends Biochem.
Sci 1996, 21, 375-382; f) X. Zhao, F. Pan, J. R. Lu, Prog. Nat. Sci - Mater.
Int. 2008, 18, 653-660; g) M. A. Dolan, P. N. Basa, O. Zozulia, Z. Lengyel,
R. Lebl, E. M. Kohn, S. Bhattacharya, I. V. Korendovych, ACS Nano 2019,
13, 9292-9297.
[8]
[9]
O. F. Brandenberg, R. Fasan, F. H. Arnold, Curr. Opin. Biotechnol. 2017,
47, 102-111.
a) G. Blauer, N. Sreerama, R. W. Woody, Biochemistry 1993, 32, 6674-
6679; b) M. Nagai, N. Mizusawa, T. Kitagawa, S. Nagatomo, Biophys.
Rev. 2018, 10, 271-284; c) M. Nagai, Y. Nagai, K. Imai, S. Neya, Chirality
2014, 26, 438-442; d) I. V. Korendovych, A. Senes, Y. H. Kim, J. D. Lear,
H. C. Fry, M. J. Therien, J. K. Blasie, F. A. Walker, W. F. DeGrado, J.
Am. Chem. Soc. 2010, 132, 15516-15518.
[3]
a) O. Zozulia, M. A. Dolan, I. V. Korendovych, Chem. Soc. Rev. 2018,
47, 3621-3639; b) Z. S. Al-Garawi, B. A. McIntosh, D. Neill-Hall, A. A.
Hatimy, S. M. Sweet, M. C. Bagley, L. C. Serpell, Nanoscale 2017, 9,
10773-10783; c) M. P. Friedmann, V. Torbeev, V. Zelenay, A. Sobol, J.
Greenwald, R. Riek, PLOS ONE 2015, 10, e0143948; d) J. L. Heier, D.
J. Mikolajczak, C. Böttcher, B. Koksch, J. Pept. Sci. 2017, 108, e23003;
e) T. Q. Luong, N. Erwin, M. Neumann, A. Schmidt, C. Loos, V. Schmidt,
M. Fändrich, R. Winter, Angew. Chem. Int. Ed. 2016, 55, 12412-12416;
f) O. Monasterio, E. Nova, R. Diaz-Espinoza, Biochem. Biophys. Res.
Commun. 2017, 482, 1194-1200; g) T. O. Omosun, M.-C. Hsieh, W. S.
Childers, D. Das, A. K. Mehta, N. R. Anthony, T. Pan, M. A. Grover, K.
M. Berland, D. G. Lynn, Nat. Chem. 2017, 9, 805-809; h) N. Singh, M.
Kumar, J. F. Miravet, R. V. Ulijn, B. Escuder, Chem. Eur. J. 2017, 23,
981-993; i) L. A. Solomon, J. B. Kronenberg, H. C. Fry, J. Am. Chem.
Soc. 2017, 139, 8497-8507; j) C. Zhang, R. Shafi, A. Lampel, D.
MacPherson, C. G. Pappas, V. Narang, T. Wang, C. Maldarelli, R. V.
Ulijn, Angew. Chem. Int. Ed. 2017, 56, 14511-14515; k) P. Makam, S. S.
[10] D. M. Carminati, R. Fasan, ACS Catal. 2019, 9, 9683-9697.
[11] a) M. Bordeaux, V. Tyagi, R. Fasan, Angew. Chem. 2015, 127, 1764-
1768; b) L. Villarino, K. E. Splan, E. Reddem, L. Alonso-Cotchico, C.
Gutiérrez de Souza, A. Lledós, J.-D. Maréchal, A.-M. W. H. Thunnissen,
G. Roelfes, Angew. Chem. Int. Ed. 2018, 57, 7785-7789.
[12] a) O. Carny, E. Gazit, FASEB J. 2005, 19, 1051-1055; b) J. Greenwald,
R. Riek, J. Mol. Biol. 2012, 421, 417-426; c) C. P. J. Maury, Orig. Life
Evol. Biosph. 2009, 39, 141-150.
[13] a) P. S. Coelho, Z. J. Wang, M. E. Ener, S. A. Baril, A. Kannan, F. H.
Arnold, E. M. Brustad, Nat. Chem. Biol. 2013, 9, 485-487.
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10.1002/anie.201916712
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Dr. Oleksii Zozulia, Prof. Dr. Ivan V.
Korendovych*
Catalysis through self-assembly: Self-
assembled nanostructures formed by semi-
rationally designed seven-residue peptides
and hemin catalyze efficient formation of
cyclopropanes in an enantioselective manner.
Page No. – Page No.
Semi-Rationally Designed Short
Peptides Self-Assemble and Bind
Hemin to Promote Cyclopropanation
This article is protected by copyright. All rights reserved.