Proximity-Induced Cooperative Polymerization in "hinged" Helical Polypeptides

Article abstract of DOI:10.1021/jacs.9b02298

Cooperative interactions and transitions are among the most important strategies utilized by biological systems to regulate a variety of physical and chemical processes. We report herein an auto-accelerated, rapid cooperative polymerization of N-carboxyanhydrides (NCAs) with initiators structurally as simple as linear aliphatic diamines for the synthesis of polypeptides. The polymerization initiated by diamines proceeds via the formation of "hinged" polypeptides, which are two blocks of helical chains connected head-to-head by the diamine molecules in the polymerization solution. The reactions follow a two-stage, cooperative polymerization kinetic; the cooperative interactions between the macrodipoles of the two hinged helical polypeptides dramatically accelerate the polymerization. Compared to the NCA polymerization initiated by the hexylamine (CH₃(CH₂)₅NH₂), the chain propagation rate of the NCA polymerization is increased by more than 600 times when initiated by its diamine analogue (1,6-diaminohexane, NH₂(CH₂)₆NH₂). This proximity-induced cooperative polymerization showcases the single helix as a remarkable cooperativity-enabling motif in synthetic chemistry.

Full text of DOI:10.1021/jacs.9b02298

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Communication
Proximity-Induced Cooperative Polymerization
in “Hinged” Helical Polypeptides
Chongyi Chen, Hailin Fu, Ryan Baumgartner, Ziyuan Song, Yao Lin, and Jianjun Cheng
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02298 • Publication Date (Web): 23 Apr 2019
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Proximity-Induced Cooperative Polymerization in “Hinged” Helical Pol-
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Chongyi Chen* , Hailin Fu , Ryan Baumgartner , Ziyuan Song , Yao Lin* and Jianjun Cheng*
†Ningbo Key Laboratory of Specialty Polymers, Faculty of Materials Science and Chemical Engineering, Ningbo Univer-
sity, Ningbo 315211, China.
‡
§
⊥
║
Department of Materials Science and Engineering, Department of Chemistry, Department of Bioengineering, Beck-
∇
O
man Institute for Advanced Science and Technology, Frederick Seitz Materials Research Laboratory, and Carl R.
Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United
States.
#
Department of Chemistry and Polymer Program at the Institute of Materials Science, University of Connecticut,
Storrs, Connecticut 06269, United States.
Supporting Information Placeholder
polymerization has been slow. While the two-stage polymeri-
zations (nucleation-growth) have been reported in the ring-
ABSTRACT: Cooperative interactions and transitions are
amongst the most important strategies utilized by biological
systems to regulate a variety of physical and chemical pro-
cesses. We report herein an auto-accelerated, rapid coopera-
tive polymerization of N-carboxyanhydrides (NCAs) with initi-
ators structurally as simple as linear aliphatic diamines for the
synthesis of polypeptides. The polymerization initiated by dia-
mines proceeds via the formation of “hinged” polypeptides –
two blocks of helical chains connected head-to-head by the di-
amine molecules in the polymerization solution. The reactions
follow a two-stage, cooperative polymerization kinetic; the co-
operative interactions between the macrodipoles of the two
hinged helical polypeptides dramatically accelerate the
polymerization. Compared to the NCA polymerization initiated
opening polymerization of N-carboxyanhydrides (NCAs) into
2
1-22
α-helical polypeptides,
the acceleration of polymerization
rate in the second stage (e.g., due to the formation of helical
chain and additional secondary interactions) was modest. Fur-
ther exploration of cooperative mechanism in the covalent
2
3-24
polymerization process remains scarce.
Recently, we discovered an auto-accelerated polymerization of
α-helical polypeptides in the brush-like macromolecular archi-
tecture, where the cooperative interactions between the
macrodipoles of neighboring helical polypeptide dramatically
accelerate the ring-opening polymerization of NCAs.25 While
this brush system clearly demonstrated that the “tertiary”
structure of the brush polymers could lead to a drastic acceler-
ation in polypeptide growth, it is of great interest to identify the
minimal complexity in macromolecular architectures that may
still facilitate this effect. For example, if there exist only two α-
helical polypeptides in proximity to one another (e.g., polymer-
ization from two initiators linked by a molecular spacer, a
by the hexylamine (CH
3
(CH
2
)
5
NH ), the chain propagation rate
2
of the NCA polymerization is increased by more than 600 times
when initiated by its diamine analogue (1,6-diaminohexane,
NH
2
(CH
2
)
6
NH ). This proximity-induced cooperative polymer-
2
ization showcases the single helix as a remarkable cooperativ-
ity-enabling motif in synthetic chemistry.
“hinged” architecture), would cooperative polymerization still
exist and the polymerization rates still be accelerated in this
very simple, dipeptide bundle “tertiary” structure? Herein, we
report the discovery of dramatic acceleration of the polymeri-
zation enabled by a motif as simple as a single polypeptide helix
hinged in proximity to the propagating polypeptide chain.
Biological macromolecules such as actin and tubulin utilize a
two-stage, nucleation-controlled cooperative polymerization
mechanism to accelerate their supramolecular assembly pro-
1
-4
cess. The cooperativity stems from the gain of additional in-
teractions among the protein subunits when they organize into
a helical supramolecular assembly instead of a linear assem-
Aliphatic diamines are ideal initiators to form the expected
“hinged” polypeptide structures in order to test whether a sin-
gle polypeptide helix has sufficient structural effect in acceler-
ating the polymerization of the covalently connected neighbor-
5
-7
bly. Progress has been reported for the design and utilization
of synthetic subunits to carry out cooperative polymerizations
for well-defined supramolecular structures and functional su-
2
6-29
ing polypeptide chain, as depicted in Figure 1a.
,6-diaminohexane (C -diNH ) for the polymerization of γ-ben-
zyl- -glutamate N-carboxyanhydride (BLG-NCA) in dichloro-
methane (DCM) (Figure 1a; entry 4, Table 1; Table S1). Under
the experimental condition of [M] = 0.10 M and [M] /[I] = 50,
the polymerization initiated by C -diNH finished in 40 min
(red curve, Figure 1b). In contrast, the control polymerization
initiated by C -NH , the monoamine analogue of C -diNH ,
We used
1
6
2
8-12
pramolecular materials.
alization of living supramolecular polymerization
equilibrium supramolecular polymerization from synthetic
Some recent studies include the re-
L
1
3-14
and non-
0
0
0
1
5
molecules, and the elucidation of the pathway complexity in
the cooperative polymerization.
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1
6-20
In contrast, the progress
in incorporating a cooperative mechanism into covalent
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showed less than 10% of the BLG-NCA consumption in the
helical macrodipole was either eliminated by using racemic
monomers or reduced by using polar solvents with higher die-
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same period (blue curve, Figure 1b). In both reactions, the
polymerization kinetics can be divided into two stages: a rela-
tively slow “nucleation” stage in which the NCA monomers are
added into short coil chains (apparent rate constants kapp1, Ta-
ble S2), followed by a fast “growth” stage in which the mono-
mers are added into helical chains (DP > 8~12) (apparent rate
2
5
lectric constant than DCM. Figure 2a shows the polymeriza-
tion of racemic NCA monomers (BDLG-NCA) from C -diNH .
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2
The use of racemic monomers prevents the formation of α-he-
lix in the resulting polypeptide chains, resulting in the loss of
the second-stage, accelerated polymerization. In addition, ef-
fects stemming from the electrostatic nature of the macrodi-
pole should vary with the dielectric constant of the solvent,
which is clearly evidenced in Figure 2b. Polymerization of BLG-
3
0-32
constants kapp2, Table S2).
The onset of the second stage al-
ways coincides with the formation of helical chains, as evi-
-1
denced by the shift of IR absorbance from 1658 cm (random
-
1
33
coil) to 1653 cm (α-helix) (Figure 1c and Figure S1). The rate
acceleration (kapp2/ kapp1) of the polymerization initiated by C
NH was found to be modest, with a 4 fold increase in the ap-
NCA by C
6
-diNH in solvent with lower dielectric constants
2
6
-
showed greater polymerization rate. In DMF, a polar solvent
with high dielectric constant (ε = 38), the two-stage character-
istic of the polymerization disappeared, substantiating the im-
portance of solvent in maintaining the helical structure for the
intended macrodipole which is essential to the acceleration of
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parent rate constant upon the formation of α-helices (entry 1,
Table S2). In contrast, the apparent polymerization rate upon
forming α-helices increased 38 times when C
6
-diNH was used
2
26
as the initiator (entry 4, Table S2), forming hinged PBLGs with
two growing arms. This drastic rate increase indicates strong
effects on the NCA polymerization by having two helical
macrodipoles located in proximity.
the polymerization. The polymerization in THF, although
with a lower dielectric constant (ε = 7.5) than DCM, is slower
than the polymerization in DCM, likely due to the interfere of
THF with the hydrogen bonds of helical polypeptide thus slow-
ing down the NCA polymerization.
Figure 2. (a) Conversion of BLG-NCA and BDLG-NCA as meas-
ured by FTIR in DCM using C
M, [M] /[I] = 50). (b) Conversion of BLG-NCA as measured by
IR in DCM (dielectric constant ε = 9.10), chloroform (ε = 4.81),
and DMF (ε = 38) initiated by C -diNH ([M] = 0.10 M, [M] /[I]
50).
6
-diNH
2
as initiators ([M] = 0.10
0
0
0
6
2
0
0
0
=
Figure 1. (a) Polymerization of BLG-NCA initiated by C
and C -NH and schematic illustration of “Hinged” polypeptides
and single polypeptides. (b) Conversion of BLG-NCA as meas-
ured by FTIR in DCM using 1,6-diaminohexane (C -diNH ) and
hexylamine (C -NH ) as initiators ([M] = 0.10 M, [M] /[I] = 50)
6
-diNH
2
6
2
6
2
6
2
0
0
0
showing remarkable rate enhancement. (c) Changes in the con-
centration of BLG-NCA and PBLG in the FTIR spectrum over the
duration of the polymerization of BLG-NCA initiated by C
diNH
6
-
2
.
Table 1. Polymerization of BLG-NCA in DCM ([M]
0
= 0.10 M).
/M
a
Entry
Initiator
-NH
[M]
0
/[I]
0
M
n
(kDa)
M
w
n
1
2
3
4
5
6
7
C
6
2
50
50
50
50
50
50
50
14.9
1.14
1.15
1.10
1.10
1.12
1.13
1.11
C
C
C
C
2
4
6
8
-diNH
-diNH
-diNH
-diNH
2
2
2
2
44.0
47.9
43.4
42.9
35.0
35.2
Figure 3. (a) Kinetic data (circles) obtained from the polymer-
ization of BLG-NCA using C -diNH (n = 2, 4, 6, 8, 10, 12) as ini-
tiators at [M] = 0.10 M and [M] /[I] = 50 is fitted with the two-
stage kinetic model (solid lines) at s = 10. Error bars represent
standard deviations from three independent measurements. (b)
n
2
0
0
0
C10-diNH
2
2
−1
Extracted k
Representation of the proximity of macrodipoles induced
polymerization of α-helical polypeptides by C -diNH
diNH and C -NH after reaching critical chain length s = 10. The
1
, k
2
and calculated σ for different C
n
-diNH . (c)
2
C12-diNH
a
Determined via gel permeation chromatography.
6
2
, C12-
2
6
2
The rate enhancement is likely due to the proximity of parallel
positive pole is located at the actively growing N-terminus and
the direction of growth is shown as the green arrow at the end
of growing polypeptides.
aligned two macrodipoles from the α-helices, in analogy to our
2
5
recently reported polypeptide brush system. To confirm this
hypothesis, we investigated the polymerizations in which the
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shows the second-stage chain propagation rate of the NCA
polymerization is 613 times fast than that of the polymeriza-
tion initiated by C -diNH (entry 4, Table S3). It is remarkable
that such a strong cooperative behavior on chain propagation
can be induced by simply having two growing chains located in
proximity.
1
2
3
4
5
6
7
8
9
To elucidate the effect of proximity between amino groups and
hence α-helices on the polymerization rate, diamines with var-
ious spacer lengths were examined (entries 2-7, Table 1; Figure
3a; Table S1). Two-stage kinetics and significant rate enhance-
ment in the second stage were observed in all diamine initia-
tors with the length of spacer (n) from 2 to 12 (entries 2-7, Ta-
ble 1). The apparent propagation rate constants (kapp2, Table S2)
of the polymerization initiated by different diamines were well
correlated with the length of spacers, and the proximity effect
starts to disappear quickly after n > 10. This result indicates
that the proximity of the two growing helical polypeptides in
the same macromolecule plays an essential role in the rate en-
hancement of polymerization. The dependence of chain propa-
gation rate on the formation of and the distance between heli-
cal macrodipoles in the proximity of active chains reveals a
characteristic cooperative behavior in the polymerization of
these “hinged” polypeptides.
6
2
Precise control and quantitative regulation of molecular coop-
erativity is very important in biology and chemistry but is yet
to be achieved. In this study, we demonstrate the important
role of the cooperative behaviors in the synthesis of polypep-
tides, in which the ring-opening polymerization of NCAs can be
drastically accelerated simply by using aliphatic diamines as
initiators in dichloromethane. The fact that the interaction of
simply two helical chains are sufficient to facilitate strong co-
operative behavior in the polymerization suggests this type of
proximity-induced cooperative polymerization may be utilized
in the synthesis of a variety of macromolecules involving the
formation of strong macrodipoles. The simple design in this
study also provides an ideal system to calibrate the cooperative
strength and precisely determine parameters that matter in
the cooperative reaction, potentially allowing in-depth, mech-
anistic studies on the cooperative covalent polymerization.
Furthermore, bundling of helix (e.g., three- or four-helix bun-
dles and coiled coils) forms important protein structural motif,
which have regulated numerous biological activities and
shown profound impact on the ubiquitous cooperativity ob-
served in biology. In this study, we unfolded the importance of
helix as one of the remarkable cooperativity-enabling elements
in synthetic chemistry, by demonstrating that this structural
motif can self-catalyze its own formation by packing two heli-
ces in proximity.
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A cooperative growth mechanism (Oosawa’s model developed
for actin polymerization) was adapted to analyze this class of
covalent cooperative polymerizations that consist of two suc-
cessive growth stages. Distinct two-stage feature is observed
after the growing chains reach a critical length and form helices
which possess secondary interactions between monomer units
and stronger macrodipoles. In this two-stage model, reaching
the critical degree of polymerization, s, causes the propagation
constant to change from k
1
to k due to the folding of the coil
2
into an α-helix. The stepwise addition of monomer, M, onto the
active chains in the first and second stage are described in
equation (1) and (2), respectively. We denote an active poly-
∗
푖
mer of degree of polymerization i by M , where * represents
the reactive end. The kinetic cooperativity factor, following the
convention in supramolecular polymerization, can be defined
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, simula-
tions with kinetic model, GPC-LS traces and predicted DP from
a modified two-stage model of polypeptides (PDF).
as the dimensionless ratio σ = k
1
2
/k where a very small value
of σ (≪ 1) implies a highly cooperative reaction.
푘1
∗
∗
푖ꢀꢁ
푀 + M → M
ꢂ ≤ ꢃ < s
ꢃ ≥ s
(coil state)
(1)
(2)
푖
푘2
∗
∗
푖ꢀꢁ
푀 + M → M
(helix state)
푖
AUTHOR INFORMATION
Corresponding Author
* jianjunc@illinois.edu
* yao.lin@uconn.edu
The two-stage, cooperative growth model was applied to the
data obtained from the polymerization of BLG-NCA using C
NH and C -diNH (n = 2, 4, 6, 8, 10, 12) as initiators at [M]
.10 M and [M] /[I] = 50. The optimized fits for the data (solid
6
-
2
n
2
0
=
0
0
0
lines in Figure 3a) were obtained with the critical degree of
polymerization, s, to be 10 for all the samples. The rate con-
* chenchongyi@nbu.edu.cn
stants (k
tivity factor σ (σ = k
by diamine as a function of spacer length are summarized in
Figure 3b. Compared to C -NH , k of the polymerization initi-
ated by C -diNH is increased dramatically (Figure S3). By
shortening the spacers from C12-diNH to C -diNH , k only
slightly increases, while k increases 112 times, from 0.304 M
1
and k
2
) as well as the inverse of the kinetic coopera-
Notes
-1
-1
2
/k
1
) for each polymerization initiated
The authors declare no competing financial interests.
6
2
2
ACKNOWLEDGMENT
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2
J.C. acknowledges the supports from the U.S. National Science
Foundation (CHE 1709820) and National Institute of Health
(1R01CA207584). Y.L. acknowledges the supports from the
U.S. National Science Foundation (CHE-1410581 and DMR-
1809497). C.C. acknowledges the supports from the National
Natural Science Foundation of China (No. 21404062) and the
K.C. Wong Magna Fund in Ningbo University.
2
2
2
1
-
1
2
-
1
-1 -1
s
of C12-diNH
2
to 34.0 M
s
of C
6
-diNH (entries 4 and 7, Ta-
2
-1
ble S3). Furthermore, σ varies between 270 and 740 when the
diamine hydrocarbon spacer length ranges from 2 to 10 (C
2
-
-
-
diNH
diNH
diNH
2
2
2
to C10-diNH ) with highest cooperativity occurring at C
, and then decreases rapidly to 16 with the use of C12
. (entries 2-7, Table S3) The result shows that appropri-
2
6
ate proximity of the helical macrodipoles dictates the rate en-
hancement in the polymerization. We note that even in C12
-
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2
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