Hexagonally Ordered Arrays of Î±-Helical Bundles Formed from

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Hexagonally Ordered Arrays of #-Helical Bundles Formed from Peptide-Dendron Hybrids Deborah A. Barkley, Yekaterina Rokhlenko, Jeannette E. Marine, Rachelle David, Dipankar Sahoo, Matthew D. Watson, Tadanori Koga, Chinedum O. Osuji, and Jonathan G. Rudick J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09737 • Publication Date (Web): 18 Oct 2017 Downloaded from http://pubs.acs.org on October 18, 2017

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Journal of the American Chemical Society

Hexagonally Ordered Arrays of α-Helical Bundles Formed from Peptide-Dendron Hybrids Deborah A. Barkley,† Yekaterina Rokhlenko,‡ Jeannette E. Marine,†,¶ Rachelle David,† Dipankar Sahoo,† Matthew D. Watson,† Tadanori Koga,†,§ Chinedum O. Osuji,‡ and Jonathan G. Rudick†,* †

Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States Department of Chemical and Environmental Engineering, Yale University, New Haven, Connecticut 06511, United States § Department of Materials Science and Engineering, Stony Brook University, Stony Brook, New York 11794, United States ‡

ABSTRACT: Combining monodisperse building blocks that have distinct folding properties serves as a modular strategy for controlling structural complexity in hierarchically organized materials. We combine an α-helical bundle-forming peptide with selfassembling dendrons to better control the arrangement of functional groups within cylindrical nanostructures. Site-specific grafting of dendrons to amino acid residues on the exterior of the α-helical bundle yields monodisperse macromolecules with programmable folding and self-assembly properties. The resulting hybrid biomaterials form thermotropic columnar hexagonal mesophases in which the peptides adopt an α-helical conformation. Bundling of the α-helical peptides accompanies self-assembly of the peptidedendron hybrids into cylindrical nanostructures. The bundle stoichiometry in the mesophase agrees well with the size found in solution for α-helical bundles of peptides with a similar amino acid sequence.

INTRODUCTION The highly designable structure and structural diversity of the α-helical coiled coil motif draws interest to α-helical bundles as building blocks for the construction of functional nanomaterials.1,2 α-Helical bundles are discrete assemblies of two or more α-helical peptides for which robust de novo design rules are available.3 Dimeric, trimeric, and tetrameric bundles have cores that are filled by the amino acid sidechains, whereas larger assemblies of five to eight helices have an accessible lumen.4 α-Helical bundle-forming peptides are characterized by a heptad repeat in which the positions in the amino acid sequence are designated abcdefg. Positions a, c, d, and g are involved in intermolecular association of the helical peptides and can be used to design binding or catalytic sites within the bundle.5-7 While many designed α-helical bundles self-assemble into diverse nanostructures,1 absorbing monolayers of α-helical bundles on to substrates remains the most common approach to integrate α-helical bundles as functional components in materials.2 Strategies for integrating coiled coil domains into other material forms (e.g., polymers)8 should significantly broaden the utility of α-helical bundles as light harvesting and charge transporting nanostructures.2,6 Herein we describe an approach to ordering α-helical bundles in nanoscale, hexagonal arrays by grafting self-assembling dendrons to the exterior positions (i.e., b, c, and f) in the heptad repeat (Figure 1). Peptide-dendron hybrids combine molecular subunits that have distinct folding properties that can be exploited to control hierarchical assembly processes.9-13 Self-assembling dendrons that promote self-organization into two- and threedimensional mesophases14-17 are especially attractive in this context as the resulting peptide-dendron hybrids form liquid

crystalline mesophases.18,19 Appending linear dipeptides18 or cyclic peptides19 with self-assembling dendrons produces materials that form columnar mesophases in which the peptide is sequestered within a cylindrical nanostructure. Benzyl ether-type dendrons bearing peripheral alkyl groups can adopt extended conformations in which the alkyl groups segregate from the branched aromatic groups.14,16 In this extended conformation, the dendrons adopt either wedgeshaped or cone-shaped conformations. Self-assembly of wedge-shaped dendrons generates columnar structures that self-organize into periodically ordered two-dimensional lattices due to nanoscale phase segregation of the branched and peripheral groups.14b,15,20 The environment within the columnar structure formed by self-assembling dendrons is markedly different from the highly solvated environment of peptides in a lyotropic liquid crystalline mesophase.21 Peptidedendron hybrids 1–4 test whether biological folding principles are reliable in the non-biological environment of the columnar hexagonal liquid crystalline mesophase. Conjugating self-assembling dendrons to the exterior residues of an α-helix bundle-forming peptide yields peptidedendron hybrids that self-organize into a hexagonal columnar lattice (Figure 1). Analysis of the results from differential scanning calorimetry (DSC), polarized optical microscopy (POM), and small- and wide-angle X-ray scattering (SAXS/WAXS) experiments confirms the hexagonal columnar phase assignment. Infrared (IR) and circular dirchroism (CD) spectra of peptide-dendron hybrid films support that the peptide adopts an α-helical conformation to satisfy backbone hydrogen bonds. Geometric analysis of the cylindrical assemblies of a series peptide-dendron hybrids in which the dendron structure is varied reveals a remarkable agreement between the number of peptide-dendron hybrids in the cylin-

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der and the stoichiometry of the native peptide bundle in aqueous buffer.22 Incorporating α-helix bundle assemblies in self-organized nanoscale arrays increases the volume over which functional group composition can be controlled in soft materials.

Figure 1. (a) Structures of the α-helical bundle-forming peptidedendron hybrids 1–4. Amino acids are designated by singleletter codes: Y = tyrosine; L = leucine; K = lysine. (b) Schematic illustration of a hexagonally ordered array of four-helix bundles.

flash column chromatography, provided hybrids 1–4 in good yields (61%–87%). Scheme 1. Graft-to Synthesis of Peptide-dendron Hybrids 1–4

Table 1. Molecular Weight Characteristics of the Hybrids 1–4

RESULTS AND DISCUSSION Synthesis of the Peptide-Dendron Hybrids. A graft-to approach, in which dendrons are attached to the peptide, was used to prepare the peptide-dendron hybrids. Conjugating dendrons to the peptide via reaction of dendrons bearing an active ester apex group with the side-chain amino group of the lysine residues ensures that the grafting process is sitespecific (Scheme 1). The reaction proceeds exclusively at the lysine residues because the N-terminus of peptide 5 is acetylated. Among active ester reagents, pentafluorophenyl esters are notable for their stability during storage. Pentafluorophenyl esters are highly efficient acylating reagents toward amines that have been used in peptide synthesis,23 as well as for grafting polymers to proteins24 and dendrons to peptides.25 We performed the reactions using an excess of the dendritic ester ([dendron]0/[amine]0 = 1.5/1; [5]0 = 0.004 M) in a mixture of THF and DMF. The co-solvent system dissolves both the dendron and the peptide starting materials. We considered the grafting reaction complete when mass peaks for peptide 5 and partially dendronized peptide intermediates are no longer evident in MALDI-TOF mass spectra of aliquots taken from the reaction mixture. Prolonged reaction times of 1–4 d at 50 °C, followed by purification using

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hybrid

m/z a

1

10,672.0 c

Mn b

Mw/Mn b

10,500

1.05

2

8,143.9

c

8,200

1.06

3

7,740.2 d

7,420

1.06

4

d

7,150

1.05

a

5,831.5

Determined from MALDI-TOF mass spectra. bDetermined from GPC in THF (1 mL/min, 40 ºC) calibrated with polystyrene standards. c[M + Na]+ ion. d[M + Ag]+ ion. The identity and purity of 1–4 were confirmed using MALDI-TOF mass spectrometry, gel permeation chromatography (GPC), and 1H NMR spectroscopy. Peptide-dendron hybrids 1–4 are soluble in THF, CH2Cl2, and CHCl3. The masses found in MALDI-TOF mass spectra (Table 1) agreed (±1 Da) with the masses calculated for the most abundant ion. No other mass peaks were observed in the MALDI-TOF mass spectra (Figure 2a), and the hybrids eluted as symmetric peaks in GPC experiments (Figure 2b). A narrow molecular weight distribution (Mw/Mn) was calculated from the chromatogram of each hybrid (Table 1). These observations show that the obtained products are free of partially dendronized side products. The number-average molecular weight values (Mn in Table 1) calculated from the GPC elu-


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tion profiles show that the hydrodynamic radii of the peptide-dendron hybrids decrease with decreasing dendron molecular weight. The results of the synthesis and molecular characterization experiments demonstrate that pentafluophenyl esters are efficient acylating agents for high-density grafting of large dendrons to peptides.

Figure 3. Representative DSC thermograms from the cooling scans (10 ºC/min) of hybrids 1–4. Phase assignments (k = crystalline solid; Colh = hexagonal columnar (p6mm) liquid crystal; i = isotropic liquid) and transition temperatures are indicated on the plots. Figure 2. (a) MALDI-TOF mass spectra of hybrids 1–4. (b) Elution profiles of hybrids 1–4 from GPC in THF (1 mL/min; 40 ºC).

Liquid Crystal Mesomorphism. In our design of peptidedendron hybrids 1–4, we envisioned that the physical properties of the dendrons would be conferred to the hybrid. We chose the dendrons in hybrids 1–4 for their propensity to self-assemble into columnar structures that further selforganize into two-dimensional lattices.14-17 The temperaturedependent phase behavior of hybrids 1–4 was investigated to confirm this portion of our design hypothesis. Gradual softening of each hybrid was observed in POM experiments as the samples were heated at a rate of 10 ºC/min. The samples remained birefringent from room temperature up to the isotropization temperature, and a birefringent fluid phase was recovered upon cooling (Figure S2). In POM experiments, we were unable to identify a characteristic texture from which we could assign the liquid crystal phase. First-order transitions corresponding to the isotropic liquid-to-liquid crystal and liquid crystal-to-crystalline solid phase transformations were identified in DSC thermograms (Figure 3). The low-temperature transition to the crystalline phase is likely due to crystallization (packing) of the peripheral alkyl chains. Consistent with this interpretation, there is little variation in the crystallization temperature across all four hybrids. The isotropization temperature increases with the number of aromatic rings in the dendron, which indicates the importance of π-stacking to the phase segregated structure that is responsible for self-assembly and self-organization in the mesophase. The phase behavior was reversible over multiple cycles in DSC experiments (Figure S3 and Table S1). Thermotropic liquid crystalline mesophases have previously been observed in α-helical peptides only when mesogens are grafted to each residue of the peptide chain.26 The thermal analysis results support our modular design strategy employing taper-shaped dendrons.

Figure 4. Plots of the (a) small-angle X-ray profiles of hybrids 1 (185 ºC), 2 (135 ºC), 3 (150 ºC), and 4 (140 ºC) and (b) wide-angle X-ray profiles of hybrids 1–4 (25 ºC). X-ray scattering experiments revealed that hybrids 1–4 each formed a columnar hexagonal liquid crystalline phase. Small- and wide-angle X-ray scattering patterns were acquired from samples sandwiched between Kapton tape with an O-ring spacer after cooling the sample from the isotropic melt phase to the mesophase (Figure 4). Discrepancies between the phase transition temperatures in DSC experiments (Figure 3 and Table S1) and the temperatures at which the SAXS patterns were acquired (Figure 4a) reflect differences between the instruments. Three sharp peaks appeared at lower q-values and in the characteristic ratio 1 : √3 : 2 which leads to their assignment as q100, q110, and q200 from a hexag-



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onal (p6mm) lattice. A diffuse peak (dalkyl = 2π/q ~ 4.5 Å) corresponding to the melted peripheral alkyl chains was observed in the wide-angle scattering patterns. These results demonstrate that the self-assembling dendrons serve their intended role for organizing the peptides into a columnar array by adopting a conformation that promotes nanoscale segregation of the aliphatic and benzyl ether parts of the dendrons. Analysis of the Peptide Conformation. A key question that we sought to answer is whether the peptide backbone adopts an α-helical conformation. None of the features in the SAXS/WAXS patterns could be assigned to the peptide structure. Techniques commonly used to identify the conformation of peptides in solution include IR and CD spectroscopies.27 Spectra from a peptide very similar in sequence to peptide 5 (i.e., Fmoc-LKKLLKLLKKLLKL-CO2H) show that there is good agreement between spectra acquired from samples in solution and in monolayer films.22a In order to confirm the secondary structure of the peptide, IR and CD spectroscopy experiments were performed on films of the hybrids as well as on films of 5. Peptide 5 serves as a control experiment with which we can characterize the spectral features of the α-helical bundleforming peptide in films. In aqueous buffer solution, peptide 5 folds and self-assembles in to an α-helical bundle.12 Films of peptide 5 were cast from MeOH for IR spectroscopy experiments, and from 2,2,2-trifluoroethanol for CD spectroscopy experiments. The amide I and amide II bands appear at 1650 cm–1 and 1545 cm–1, respectively, in the IR spectrum of 5 (Figure 5a). Typical values for the amide I and II bands of α-helical peptides and proteins are 1657–1652 cm–1 and 1551–1545 cm–1, respectively.27a The shape of the CD spectrum in Figure 5b is similar to spectra of α-helical peptides in solution. α-Helical peptides are identified from a maximum at 190 nm (perpendicular-polarized π-π* exciton transition) and minima at 208 nm (parallel-polarized π-π* exciton transition) and 222 nm (n-π* transition) in CD spectra.28 The IR and CD spectra of 5 (Figure 5) confirm that the peptide adopts an α-helical conformation in films just like monolayer films of the α-helical bundle-forming peptide FmocLKKLLKLLKKLLKL-CO2H.22a

Figure 5. (a) Infrared and (b) circular dichroism spectra of peptide 5 in a film.

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Figure 6. Infrared spectra of hybrids 1–4 acquired at room temperature from as-cast films (red curves) and from films that were annealed at 5 °C below the isotropization temperature for 10 min (blue curves).

Assignments of the amide I and amide II bands in the IR spectra of hybrids 1–4 indicate that the peptide adopts an αhelical conformation. Films of the hybrids were cast from solution on a salt plate. The IR spectra of the films were measured at room temperature. In the region between 1700– 1580 cm–1 (Figure 5), we observed several bands arising from the C=O stretching (amide I), C=C stretching in aromatic rings, and N–H in-plane bending (amide II) modes. The C=C stretching modes depended on the branching pattern of the dendrons, whereas the C=O stretching (1655– 1651 cm–1) and N–H in-plane bending (1545 cm–1) modes were independent of the dendron structure. The IR spectra acquired after annealing the films in the liquid crystalline mesophase were identical to the as-cast films (Figure 6), which suggested that the α-helical conformation remains unchanged during heating and cooling cycles. The CD spectra obtained from films of the hybrids are similar to the CD spectra of α-helical peptides. Films of hybrids 1–4 were spin-cast from solution onto quartz slides. The films were inspected using an optical microscope to ensure that the films were uniform (Figure S4), and the thickness of each film was determined from ellipsometry measurements (360–380 nm thick). We observed a maximum at 192–195 and minima at 208–210 nm and 219–227 nm in the CD spectra of the hybrids 1–4 (Figure 7). These features agree well with the spectral features of α-helical peptides lying parallel to the substrate on which the films are cast (Figures S5 and S6).29 Linear dichroism due to anisotropy of the mesophase can manifest as artifacts in CD spectra. We confirmed that the films were optically isotropic using POM (Figure S4). The films were rotated 90º and 180º, and very little change was observed in the acquired spectra (Figure S7). Annealing the samples in the isotropic melt phase produced small changes in the CD spectra, but the characteristic maximum and minima were still present (Figure S8). These observations indicate that the circular


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Figure 7. Circular dichroism spectra (upper curve, left-hand axis) and UV-Vis spectra (lower curve, right-hand axis) from films of (a) 1, (b) 2, (c) 3, and (d) 4. Spectra were recorded at 20 °C. dichroism originates in the chirality of the hybrid molecules, g/cm3. This assumption is based on experimentally deterrather than the structure of the mesophase, and confirm the mined densities reported for self-assembling dendritic dipepformation of α-helical bundles in the mesophase. tides.18d-g,18i The calculated values of µ range from 4.1 to 4.6 and are reported in Table 2. Rather than assuming a value for Chromophores that absorb strongly in the far-UV region ρ, we also calculated the density for assumed values of µ (e.g., aromatic groups) can enhance or alter the observed CD 30 (Table S3). Two- (µ = 2) and three-helix (µ = 3) bundle asspectrum from a peptide or protein. Transfer of chirality semblies yielded unreasonably low densities (i.e., ρ ~ 0.5 from the peptide to the dendrons appears to be present in the g/cm3 and ρ ~ 0.7 g/cm3, respectively). Reasonable values CD spectra of hybrids 1–4 (Figure 7). The intensity of the for ρ were obtained when µ = 4 (ρ ~ 0.9 g/cm3) and when µ = observed CD signal is inversely proportional to the fraction 5 (ρ ~ 1.1 g/cm3). Allowing for interhelical crossing angles of peptide in the series 1–4. This is most apparent when of 15º-30º, similar to those found in crystal structures of αcomparing the low-wavelength maxima in the spectra of 2 helical bundles,32 increases the calculated values of ρ for and 3 (Figure 7b,c) where the UV absorbance is nearly ideneach bundle size. Either geometrical analysis of the columtical for the two films. The intensity of the maximum is nar hexagonal mesophase indicates that bundles of four or greater for 3. Hybrid 3 has a more electron-rich aromatic five α-helices are sequestered in the center of the columns. ring attached to the lysine side chain and an additional aromatic ring compared to the dendrons in 2. The amide and Table 2. Structural Analysis of the Columnar Assemblies aromatic chromophores in hybrids 1–4 are in an asymmetric of Hybrids 1–4 environment consistent with the peptide adopting an hybrid q100 q110 q200 T a µc α-helical conformation. –1 –1 –1 a b (Å ) (Å ) (Å ) (ºC) (Å) Stoichiometry of the Helix Bundle Assemblies. When peptide-dendron hybrids 1–4 self-assemble into cylindrical 1 0.11 0.19 0.22 185 67 4.1 objects that make up the columnar hexagonal lattice, the d – 0.19 0.22 25 peptides should be sequestered as a bundle of α-helices at the d 2 0.12 0.22 – 135 59 4.2 core of the cylinder. The taper-shaped dendrons are disd played on one face of the helix when the peptide adopts an – 0.22 0.25 25 α-helical conformation. The hybrids, then, have an overall 3 0.12 0.21 –d 150 60 4.6 tapered shape with the α-helical peptide at the apex. The d – 0.20 0.24 25 number of peptide-dendron hybrids (µ) that make up a cylindrical unit within the hexagonal lattice corresponds to the 4 0.14 –d –d 140 50 4.5 d helix bundle stoichiometry in the mesophase. Geometric – 0.26 0.29 25 analyses that assume either the density of the material or the a Temperature at which the SAXS/WAXS patterns were recordstoichiometry of the bundle indicate that bundles of four or ed. bLattice parameter a = (4π/√3)((1/q100)+(√3/q110)+(2/q200))/3. five α-helices are present in the liquid crystalline mesophase. c The number of peptide-dendron hybrid molecules in a column The α-helical bundles stack end-to-end31 to form the columstratum = (πa2lρNA)/(4M) where l = 21 Å, ρ is the density (asnar structures that self-organize into the hexagonal lattice. sumed to be 1 g/cm3), NA = 6.022 x 1023, and M is the molecular For each peptide-dendron hybrid, we determined a cylinweight of the hybrid. dThese reflections appear outside the qdrical unit cell volume. The center-to-center distance berange of the experiment. tween columns (a) was calculated as an average from all the The calculated values of µ (Table 2) can be compared with available SAXS/WAXS data (Table 2) to determine the dithe stoichiometry of closely related bundle-forming peptides ameter of the cylindrical object in the lattice (Dcol). The in solution. We employed a rudimentary design principle number of layers of benzyl ether units in hybrids 1–4 is pri(i.e., hydrophobic patterning) when selecting the amino acid marily responsible for the variation of a (Table 2). From the sequence for peptide 5.12 The stoichiometry of the helix bunpitch of an α-helix (1.5 Å/amino acid) and the number of dle assembly formed by 5 in aqueous solution has not been amino acids in the peptide, we estimated the length (l) of the determined, but Fmoc-LKKLLKLLKKLLKL-CO2H forms a assembly to be 21 Å. four-helix bundle22a and Ac-LKKLLKLLKKLLKL-CONH2 The number of peptide-dendron hybrids (µ) that occupy forms bundles of three to five α-helices.22b The poor specificthe cylindrical unit cell volume is related to the density (ρ) of ity of these peptides for a unique bundle size is due, in part, the material. We calculated values of µ for a cylinder of to the presence of Leu residues at the a- and d-positions in length = 21 Å and diameter equal to a by assuming that ρ = 1



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the heptad repeat. We observe bundle stoichiometry (µ) values in the liquid crystalline mesophase that correspond to the bundle sizes observed in solution. More carefully designed peptides are expected to further demonstrate that the selfassembly program encoded in the amino acid sequence persists in the liquid crystalline mesophase.

CONCLUSION Self-organized arrays of α-helical bundles offer templates with which short-range order and functional group diversity can be programmed in soft materials. The expanding array of α-helical coiled coil structures that have been designed de novo3-7 highlights the fidelity of biological folding and selfassembly principles. Moreover, functional properties designed to mimic or expand on those of natural proteins are available among these de novo designed α-helical bundles.2,4c,5-7 The experiments described above help to address the question of whether those de novo design rules translate to non-biological environments. Indeed, the αhelical bundle-forming peptide-dendron hybrids 1–4 selfassemble into columnar structures in which four or five αhelical peptides bundle together. The amino acid side chains that make up the core of the cylindrical nanostructure are fully addressable through changes to the amino acid sequence. Changes to the amino acid sequence should provide a reliable mechanism to vary the stoichiometry of the bundle4 and to endow the cylindrical nanostructures with binding, mass transport, catalytic, or light harvesting functions.2,4c,5-7

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. MALDI-TOF mass spectra and GPC elution profiles for 6– 9, POM images, complete DSC data, tabulated IR frequencies for the amide I and amide II bands, optical micrographs of films, GISAXS of 1 on quartz, fitting of CD spectra, additional CD spectra, calculated density for bundles with varied stoichiometry, detailed experimental procedures, and NMR spectra (PDF)

AUTHOR INFORMATION Corresponding Author * [email protected]

Present Addresses ¶

Current address: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854

ACKNOWLEDGMENT Acknowledgement is made to the National Science Foundation (DMR-1255245 (J.G.R), DMR-1410568 (C.O.O.), CMMI1332499 (T.K.), and MCB-1330259 (D.P.R.)) for support of this research. Y.R. acknowledges support from a National Physical Science Consortium Fellowship. We also thank Prof. Daniel P. Raleigh (Stony brook University) for providing access to a circular dichroism spectrometer. This research used the Complex Materials Scattering (CMS) beamline of the National Synchrotron Light Source II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science

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by Brookhaven National Laboratory under Contract No. DESC0012704.

REFERENCES (1) (a) Burgess, N. C.; Sharp, T. H.; Thomas, F.; Wood, C. W.; Thomson, A. R.; Zaccai, N. R.; Brady, R. L.; Serpell, L. C.; Woolfson, D. N., J. Am. Chem. Soc. 2015, 137, 10554-10562; (b) Thomas, F.; Burgess, N. C.; Thomson, A. R.; Woolfson, D. N., Angew. Chem., Int. Ed. 2016, 55, 987-991; (c) Fletcher, J. M.; Harniman, R. L.; Barnes, F. R. H.; Boyle, A. L.; Collins, A.; Mantell, J.; Sharp, T. H.; Antognozzi, M.; Booth, P. J.; Linden, N.; Miles, M. J.; Sessions, R. B.; Verkade, P.; Woolfson, D. N., Science 2013, 340, 595-599; (d) Anzini, P.; Xu, C.; Hughes, S.; Magnotti, E.; Jiang, T.; Hemmingsen, L.; Demeler, B.; Conticello, V. P., J. Am. Chem. Soc. 2013, 135, 10278-10281; (e) Xu, C.; Liu, R.; Mehta, A. K.; Guerrero-Ferreira, R. C.; Wright, E. R.; DuninHokawicz, S.; Morris, K.; Serpell, L. C.; Zuo, X.; Wall, J. S.; Conticello, V. P., J. Am. Chem. Soc. 2013, 135, 15565-15578; (f) Magnotti, E. L.; Hughes, S. A.; Dillard, R. S.; Wang, S.; Hough, L.; Karumbamkandathil, A.; Lian, T.; Wall, J. S.; Zuo, X.; Wright, E. R.; Conticello, V. P., J. Am. Chem. Soc. 2016, 138, 16274-16282; (g) Zhang, H. V.; Polzer, F.; Haider, M. J.; Tian, Y.; Villegas, J. A.; Kiick, K. L.; Pochan, D. J.; Saven, J. G., Sci. Adv. 2016, 2, e1600307; (h) Brodin, J. D.; Smith, S. J.; Carr, J. R.; Tezcan, F. A., J. Am. Chem. Soc. 2015, 137, 10468-10471. (2) (a) Krishnan, V.; Tronin, A.; Strzalka, J.; Fry, H. C.; Therien, M. J.; Blasie, J. K., J. Am. Chem. Soc. 2010, 132, 11083-11092; (b) Gonella, G.; Dai, H.-L.; Fry, H. C.; Therien, M. J.; Krishnan, V.; Tronin, A.; Blasie, J. K., J. Am. Chem. Soc. 2010, 132, 9693-9700; (c) Katz, E.; Heleg-Shabtai, V.; Willner, I.; Rau, H. K.; Haehnel, W., Angew. Chem., Int. Ed. 1998, 37, 3253-3256; (d) Willner, I.; Heleg-Shabtai, V.; Katz, E.; Rau, H. K.; Haehnel, W., J. Am. Chem. Soc. 1999, 121, 6455-6468. (3) (a) Apostolovic, B.; Danial, M.; Klok, H.-A., Chem. Soc. Rev. 2010, 39, 3541-3575; (b) Woolfson, D. N., Adv. Protein Chem. 2005, 70, 79-112. (4) (a) Zaccai, N. R.; Chi, B.; Thomson, A. R.; Boyle, A. L.; Bartlett, G. J.; Bruning, M.; Linden, N.; Sessions, R. B.; Booth, P. J.; Brady, R. L.; Woolfson, D. N., Nat. Chem. Biol. 2001, 7, 935941; (b) Thomson, A. R.; Wood, C. W.; Burton, A. J.; Bartlett, G. J.; Sessions, R. B.; Brady, R. L.; Woolfson, D. N., Science 2014, 346, 485-488; (c) Mahendran, K. R.; Niitsu, A.; Kong, L.; Thomson, A. R.; Sessions, R. B.; Woolfson, D. N.; Bayley, H., Nat. Chem. 2017, 9, 411-419. (5) (a) Burton, A. J.; Thomson, A. R.; Dawson, W. M.; Brady, R. L.; Woolfson, D. N., Nat. Chem. 2016, 8, 837-844; (b) Joh, N. H.; Wang, T.; Bhate, M. P.; Acharya, R.; Wu, Y.; Grabe, M.; Hong, M.; Grigoryan, G.; DeGrado, W. F., Science 2014, 346, 1520-1524. (6) (a) Korendovych, I. V.; Senes, A.; Kim, Y. H.; Lear, J. D.; Fry, H. C.; Therien, M. J.; Blasie, J. K.; Walker, F. A.; DeGrado, W. F., J. Am. Chem. Soc. 2010, 132, 15516-15518; (b) Fry, H. C.; Lehmann, A.; Sinks, L. E.; Asselberghs, I.; Tronin, A.; Krishnan, V.; Blasie, J. K.; Clays, K.; DeGrado, W. F.; Saven, J. G.; Therien, M. J., J. Am. Chem. Soc. 2013, 135, 13914-13926. (7) (a) Bialas, C.; Jarocha, L. E.; Henbest, K. B.; Zolitsch, T. M.; Kodali, G.; Timmel, C. R.; Mackenzie, S. R.; Dutton, P. L.; Moser, C. C.; Hore, P. J., J. Am. Chem. Soc. 2016, 138, 16584-16587; (b) Farid, T. A.; Kodali, G.; Solomon, L. A.; Lichtenstein, B. R.; Sheehan, M. M.; Fry, B. A.; Bialas, C.; Ennist, N. M.; Siedlecki, J. A.; Zhao, Z.; Stetz, M. A.; Valentine, K. G.; Anderson, J. L. R.; Wand, A. J.; Discher, B. M.; Moser, C. C.; Dutton, P. L., Nat. Chem. Biol. 2013, 9, 826-833. (8) (a) Presley, A. D.; Chang, J. J.; Xu, T., Soft Matter 2011, 7, 172-179; (b) Shu, J. Y.; Panganiban, B.; Xu, T., Ann. Rev. Phys. Chem. 2013, 64, 631-657; (c) Klok, H.-A.; Vandermeulen, G. W. M.; Nuhn, H.; Rösler, A.; Hamley, I. W.; Castelletto, V.; Xu, H.; Sheiko, S. S., Faraday Discuss. 2005, 128, 29-41; (d) Babin, J.; Rodriguez-Hernandez, J.; Lecommandoux, S.; Klok, H.-A.; Achard, M.-F., Faraday Discuss. 2005, 128, 179-192.


Page 7 of 8

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(9) (a) Jang, W.-D.; Jiang, D.-L.; Aida, T., J. Am. Chem. Soc. 2000, 122, 3232-3233; (b) Sato, K.; Itoh, Y.; Aida, T., Chem. Sci. 2014, 5, 136-140. (10) (a) Shao, H.; Lockman, J. W.; Parquette, J. R., J. Am. Chem. Soc. 2007, 129, 1884-1885; (b) Shao, H.; Parquette, J. R., Angew. Chem., Int. Ed. 2009, 48, 2525-2528; (c) Shao, H.; Bewick, N. A.; Parquette, J. R., Org. Biomol. Chem. 2012, 10, 2377-2379. (11) (a) Chen, X.; He, Y.; Kim, Y.; Lee, M., J. Am. Chem. Soc. 2016, 138, 5773-5776; (b) Park, I.-S.; Yoon, Y.-R.; Jung, M.; Kim, K.; Park, S.; Shin, S.; Lim, Y.-b.; Lee, M., Chem. - Asian J. 2010, 6, 452-458; (c) Moon, K.-S.; Lee, E.; Lim, Y.-b.; Lee, M., Chem. Commun. 2008, 4001-4003; (d) Lim, Y.-B.; Lee, E.; Lee, M., Angew. Chem., Int. Ed. 2007, 46, 9011-9014. (12) (a) Marine, J. E.; Song, S.; Liang, X.; Watson, M. D.; Rudick, J. G., Chem. Commun. 2015, 51, 14314-14317; (b) Marine, J. E.; Song, S.; Liang, X.; Rudick, J. G., Biomacromolecules 2016, 17, 336-344. (13) (a) Kale, T. S.; Marine, J. E.; Tovar, J. D., Macromolecules 2017, 50, 5315-5322; (b) Lee, J.; Kim, J. M.; Yun, M.; Park, C.; Park, J.; Lee, K. H.; Kim, C., Soft Matter 2011, 7, 9021-9026; (c) Zhuravel, M. A.; Davis, N. E.; Nguyen, S. T.; Koltover, I., J. Am. Chem. Soc. 2004, 126, 9882-9883. (14) (a) Balagurusamy, V. S. K.; Ungar, G.; Percec, V.; Johansson, G., J. Am. Chem. Soc. 1997, 119, 1539-1555; (b) Hudson, S. D.; Jung, H.-T.; Percec, V.; Cho, W.-D.; Johansson, G.; Ungar, G.; Balagurusamy, V. S. K., Science 1997, 278, 449-452. (15) (a) Percec, V.; Cho, W.-D.; Mosier, P. E.; Ungar, G.; Yeardley, D. J. P., J. Am. Chem. Soc. 1998, 120, 11061-11070; (b) Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P., Angew. Chem., Int. Ed. 2000, 39, 1597-1602; (c) Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P., J. Am. Chem. Soc. 2001, 123, 13021315. (16) Ungar, G.; Liu, Y.; Zeng, X.; Percec, V.; Cho, W.-D., Science 2003, 299, 1208-1211. (17) (a) Percec, V.; Cho, W.-D.; Möller, M.; Prokhorova, S.; Ungar, G.; Yeardley, D. J. P., J. Am. Chem. Soc. 2000, 122, 42494250; (b) Percec, V.; Cho, W.-D.; Ungar, G., J. Am. Chem. Soc. 2000, 122, 10273-10281; (c) Zeng, X.; Ungar, G.; Liu, Y.; Percec, V.; Dulcey, A. E.; Hobbs, J. K., Nature 2004, 428, 157-160. (18) (a) Percec, V.; Dulcey, A. E.; Balagurusamy, V. S. K.; Miura, Y.; Smidrkal, J.; Peterca, M.; Nummelin, S.; Edlund, U.; Hudson, S. D.; Heiney, P. A.; Duan, H.; Magonov, S. N.; Vinogradov, S. A., Nature 2004, 430, 764-768; (b) Percec, V.; Dulcey, A.; Peterca, M.; Ilies, M.; Miura, Y.; Edlund, U.; Heiney, P. A., Aust. J. Chem. 2005, 58, 472-482; (c) Percec, V.; Dulcey, A. E.; Peterca, M.; Ilies, M.; Ladislaw, J.; Rosen, B. M.; Edlund, U.; Heiney, P. A., Angew. Chem., Int. Ed. 2005, 44, 6516-6521; (d) Percec, V.; Dulcey, A. E.; Peterca, M.; Ilies, M.; Sienkowska, M. J.; Heiney, P. A., J. Am. Chem. Soc. 2005, 127, 17902-17909; (e) Percec, V.; Dulcey, A. E.; Peterca, M.; Ilies, M.; Nummelin, S.; Sienkowska, M. J.; Heiney, P. A., Proc. Natl. Adac. Sci. USA 2006, 103, 2518-2523; (f) Peterca, M.; Percec, V.; Dulcey, A. E.; Nummelin, S.; Korey, S.; Ilies, M.; Heiney, P. A., J. Am. Chem. Soc. 2006, 128, 6713-6720; (g) Percec, V.; Dulcey, A. E.; Peterca, M.; Adelman, P.; Samant, R.; Balagurusamy, V. S. K.; Heiney, P. A., J. Am. Chem. Soc. 2007, 129, 5992-6002; (h) Kaucher, M. S.; Peterca, M.; Dulcey, A. E.; Kim, A. J.; Vinogradov, S. A.; Hammer, D. A.; Heiney, P. A.; Percec, V., J. Am. Chem. Soc. 2007, 129, 11698-11699; (i) Percec, V.; Peterca, M.; Dulcey, A. E.; Imam, M. R.; Hudson, S. D.; Nummelin, S.; Adelman, P.; Heiney, P. A., J. Am. Chem. Soc. 2008, 130, 13079-13094; (j) Kim, A. J.; Kaucher, M. S.; Davis, K. P.; Peterca, M.; Imam, M. R.; Christian, N. A.; Levine, D. H.; Bates, F. S.; Percec, V.; Hammer, D. A., Adv. Funct. Mater. 2009, 19, 2930-2936; (k) Rosen, B. M.; Peterca, M.; Morimitsu, K.; Dulcey, A. E.; Leowanawat, P.; Resmerita, A.-M.; Imam, M. R.; Percec, V., J. Am. Chem. Soc. 2011, 133, 5135-5151. (19) (a) Sato, K.; Itoh, Y.; Aida, T., J. Am. Chem. Soc. 2011, 133, 13767-13769; (b) Amorín, M.; Pérez, A.; Barberá, J.; Ozores, H. L.; Serrano, J. L.; Granja, J. R.; Sierra, T., Chem. Commun. 2014, 50, 688-690.

(20) (a) Feng, X.; Nejati, S.; Cowan, M. G.; Tousley, M. E.; Wiesenauer, B. R.; Noble, R. D.; Elimelech, M.; Gin, D. L.; Osuji, C. O., ACS Nano 2016, 10, 150-158; (b) Feng, X.; Tousley, M. E.; Cowan, M. G.; Wiesenauer, B. R.; Siamak, N.; Choo, Y.; Noble, R. D.; Elimelech, M.; Gin, D. L.; Osuji, C. O., ACS Nano 2014, 8, 11977-11986. (21) (a) Pomerantz, W. C.; Abbott, N. L.; Gellman, S. H., J. Am. Chem. Soc. 2006, 128, 8730-8731; (b) Bellomo, E. G.; Davidson, P.; Impéror-Clerc, M.; Deming, T. J., J. Am. Chem. Soc. 2004, 126, 9101-9105; (c) Yu, S. M.; Conticello, V. P.; Zhang, G.; Kayser, C.; Fournier, M. J.; Mason, T. L.; Tirrell, D. A., Nature 1997, 389, 167170. (22) (a) DeGrado, W. F.; Lear, J. D., J. Am. Chem. Soc. 1985, 107, 7684-7689; (b) Buchko, G. W.; Jain, A.; Reback, M. L.; Shaw, W. J., Canadian Journal of Chemistry 2013, 91, 406-413. (23) (a) Kovacs, J.; Kapoor, A., J. Am. Chem. Soc. 1965, 87, 118119; (b) Kovacs, J.; Kisfaludy, L.; Ceprini, M. Q., J. Am. Chem. Soc. 1967, 89, 183-184; (c) Wathier, M.; Jung, P. J.; Carnahan, M. A.; Kim, T.; Grinstaff, M. W., J. Am. Chem. Soc. 2004, 126, 1274412745; (d) Kikkeri, R.; Hossain, L. H.; Seeberger, P. H., Chem. Commun. 2008, 2127-2129. (24) (a) McRae, S.; Chen, X.; Kratz, K.; Samanta, D.; Henchey, E.; Schneider, S.; Emrick, T., Biomacromolecules 2012, 13, 20992109; (b) Wiss, K. T.; Krishan, O. D.; Roth, P. J.; Kiick, K. L.; Theato, P., Macromolecules 2009, 42, 3860-3863. (25) Gillich, T.; Benetti, E. M.; Rakhmatullina, E.; Konradi, R.; Li, W.; Zhang, A.; Schlüter, A. D.; Textor, M., J. Am. Chem. Soc. 2011, 133, 10940-10950. (26) Cormack, P. A. G.; Moore, B. D.; Sherrington, D. C., J. Mater. Chem. 1997, 7, 1977-1983. (27) (a) Jackson, M.; Mantsch, H. M., Crit. Rev. Biochem. Mol. Biol. 1995, 30, 95-120; (b) Greenfield, N. J., Nat. Protoc. 2006, 1, 2876-2890. (28) Holzwarth, G.; Doty, P., J. Am. Chem. Soc. 1965, 87, 218228. (29) Wu, Y.; Huang, H. W.; Olah, G. A., Biophys. J. 1990, 57, 797-806. (30) Woody, R. W., Biopolymers 1978, 17, 1451-1467. (31) (a) Ogihara, N. L.; Weiss, M. S.; DeGrado, W. F.; Eisenberg, D., Protein Sci. 1997, 6, 80-88; (b) Kim, K.-H.; Ko, D.K.; Kim, Y.-T.; Kim, N. H.; Paul, J.; Zhang, S.-Q.; Murray, C. B.; Acharya, R.; DeGrado, W. F.; Kim, Y. H.; Grigoryan, G., Nat. Commun. 2016, 7, 11426. (32) (a) Kamtekar, S.; Hecht, M. H., FASEB J. 1995, 9, 10131022; (b) Walters, R. F. S.; DeGrado, W. F., Proc. Natl. Adac. Sci. USA 2006, 103, 13658-13663



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