Aromatic Motifs Dictate Nanohelix Handedness of Tripeptides - ACS

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Aromatic Motifs Dictate Nanohelix Handedness of Tripeptides Qiguo Xing, Jiaxing Zhang, Yanyan Xie, Yuefei Wang, Wei Qi, Hengjun Rao, Rongxin Su, and Zhimin He ACS Nano, Just Accepted Manuscript • DOI: 10.1021/acsnano.8b06173 • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 19, 2018

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ACS Nano

Aromatic Motifs Dictate Handedness of Tripeptides

Nanohelix

Qiguo Xing,†,# Jiaxing Zhang,†,# Yanyan Xie,‡ Yuefei Wang,*,†,‖ Wei Qi,*,†,§,‖ Hengjun Rao,† Rongxin Su,†,§,‖ Zhimi He†

† State

Key Laboratory of Chemical Engineering, School of Chemical Engineering

and Technology, Tianjin University, Tianjin 300072, P. R. China ‡

Key Laboratory of Industrial Fermentation Microbiology, Ministry of Education,

School of Biotechnology, Tianjin University of Science and Technology, Tianjin (300457), P. R. China § Collaborative

Innovation Center of Chemical Science and Engineering (Tianjin),

Tianjin 300072, P. R. China ‖ Tianjin

Key Laboratory of Membrane Science and Desalination Technology, Tianjin

University, Tianjin 300072, P. R. China. # These

authors contributed equally to this work.

* Correspondence authors: Yuefei Wang (email: [email protected]) and Wei Qi (email: [email protected]).

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ABSTRACT: Self-assembly of peptides and amyloid fibrils offers an appealing approach for creating chiral nanostructures, which has promising applications in the fields of biology and materials science. Although numerous self-assembled chiral materials have been designed, the precise control of their twisting tendency and their handedness is still a challenge. Herein, we report the self-assembly of chiral nanostructures with precisely tailored architectures by changing the amino acid sequences of the peptides. We designed a series of self-assembling tripeptides bearing different L-amino acid sequences. The peptide with L-Phe-L-Phe sequence preferred to self-assemble into left-handed nanohelices, while with L-Phe-L-Trp, right-handed nanohelices would be formed. Moreover, the diameter of the self-assembled nanohelices could be tailored by changing the terminal amino acids (His, Arg, Ser, Glu and Asp). Circular dichroism (CD) and molecular dynamics simulations (MDSs) revealed that both of the right- and left-handed nanohelices formed by the tripeptides showed negative cotton effects in the peptide adsorption region, but exhibited nearly opposite CD cotton effects in the aromatic regions. These results indicated that the handedness of the self-assembled helical nanofibers was not only determined by the chirality of the peptide backbone, but also closely related to the aromatic stacking, hydrogen bonding and steric interactions induced by the side chains. The findings deepen our understanding on the chiral self-assembly of peptide and offer opportunities for the creation of highly functional chiral nanomaterials. KEYWORDS: peptide, self-assembly, amino acid sequence, chiral nanostructures, handedness inversion 2


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Chirality is an intrinsic characteristic of living matter and ubiquitous in nature which could be observed at various levels such as subatomic, molecular, supramolecular, macroscopic, and galactic scales.1, 2 Among these levels, the rational control of chirality at supramolecular level in both biological and synthetic systems is of vital importance and has direct ramifications in various fields, including optics, biomedicine, catalysis and separation.1,

3-10

Self-assembly of peptides provides an

appealing approach to obtain supramolecular chiral materials and has been an active area of research over the past few decades.11-20 The chiral self-assembly of the amyloid polypeptides or short peptides can provide us a series of chiral nanostructures such as twist ribbons,21, 22 helical tubes9, 23 and helical ribbons.20, 24-26 The formation of such sophisticated nanostructures arises from a complex interplay among various non-covalent interactions including electrostatic interactions, hydrogen bonds, aromatic stacking as well as the steric effects. In fact, a large number of previous works have validated that the self-assembling conditions such as solvents,27, 28 pH,26, 29-31 temperature,32, 33 additives34, 35 and peptide modifications36,

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(e.g., alkyl chains, aromatic N-capping, C-terminal amidation)

could exert a profound effect on the eventual morphologies and handedness of the self-assembled materials. Our recent studies have demonstrated that the counterion and terminal charges played a crucial role in determining the structural metric and handedness of chiral nanostructures for peptides.34,

38

Correspondingly, the internal

elements including the sequences and chirality of the constituent amino acids are of vital importance for self-assembled structures and grip attention of numerous 3


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researchers.39-45 For example, Stupp and coworkers designed four peptide amphiphilic isomers adjacent to the hydrophobic alkyl with varying sequences. They found that the VEVE and EVEV with a peptide sequence of alternating hydrophobic and hydrophilic amino acids could self-assemble into flat nanostructures in which EVEV could form helical or twisted ribbon. By contrast, VVEE and EEVV could only form cylindrical nanofibers.40 Cui et al. have indicated that the peptide terminal charge plays a crucial role in affecting the nanostructure morphology by investigating the self-assembly of three different peptides, i.e., EFFFFE, KFFFFK, and EFFFFK.41 In term of rational control of the handedness of the self-assembled nanofibers, plenty of investigations focus on changing L- or D- configuration of the constituent amino acids of the peptides.46,

47

For example, Xu et al. have synthesized three pairs of short

amphiphilic peptides and demonstrated that the handedness of the self-assembled helical aggregates was controlled by the chirality of the hydrophilic lysine head.47 Moreover, recent studies even showed that both left- and right-handed chiral nanostructure could be assembled by peptides that contains only L-amine acids.20, 26, 31, 34, 35, 37

Given that almost all the amino acids in nature and human body are L-amino

acids, an in-depth understanding about the influence of amino acid sequence on the chiral self-assembly of peptides that consist of all

L-amino

acids has a wider

significance in materials and biology science. In view of these issues, we here designed five pairs of tripeptides with different sequences of the middle and terminal amino acid. These peptide molecules had a 9-fluorenylmethoxycarbonyl (Fmoc) group joined to the N-terminus of a tripeptide 4


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with a series of L-amino acids. We investigated their self-assembly process at the same condition at pH 6 and found that Fmoc-FWX (X = H, R, S, E or D) trend to form right-handed nanohelices while Fmoc-FFX (X = H, R, S, E or D) trend to form left-handed nanohelices (Scheme 1). Moreover, the diameter of the self-assembled chiral nanostructures could be further tailored by altering the terminal charges of the terminal amino acid. Molecular dynamics simulations were performed to explore the molecular conformation of Fmoc-tripeptides and suggested that the steric hindrance and aromatic stacking of the side chain and the hydrogen bonding between the side chain and water molecules might play crucial roles in determining the handedness of the self-assembled chiral nanostructures. This work highlights the effect of L-amino acid sequence patterning in short peptides on the handedness of the self-assembled nanostructures, which deepens our understanding on peptide self-assembly and provides a generic strategy for the design of highly ordered chiral nanostructures.

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Scheme 1. Schematic illustration showing the chiral self-assembly of Fmoc-FWX (X = H, R, S, E or D) or Fmoc-FFX (X = H, R, S, E or D) into chiral nanostructures with different handedness. The peptides consist of only L-amino acids.

RESULTS AND DISCUSSION The tripeptides are designed based on an aromatic dipeptide (FW or FF) protected at the N-terminus with a 9-fluorenylmethoxycarbonyl (Fmoc) group and linked at the C-terminus with a series of amino acids. Typically, we chose Phe-Trp (FW) dipeptide owing to its strong π−π association, high propensity to self-assemble13, 48 and possible applications in biological sensing.49 Correspondingly, the choice of Phe-Phe (FF) dipeptide was for its wide applications in the self-assembly of short peptides.50, 51 In term of the choices of terminal amino acids, the five amino acids differ in their terminal charges and thus give rise to distinct electrostatic interactions during the self-assembly of the tripeptides. The incorporation of Fmoc moiety arises from its wide application in solid-phase peptide synthesis and the inherent aromaticity which can promote the self-assembly of peptides.52 We firstly investigated the self-assembly of Fmoc-FWH and Fmoc-FFH at pH 6.0. The reason we chose pH 6 is that the self-assembly of peptides at this pH value may have a significance in medical applications given that many tumors exist in an acidic environment.53 The Fmoc-tripeptides were initially dissolve in an NaOH solution (pH≈10) at a concentration of 2 mM and the pH was then adjusted to 6.0 with HCl, allowing them to self-assemble at 25°C. Scanning electron microscopy (SEM), atomic 6


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force microscopy (AFM) and transmission electron microscopy (TEM) were performed to characterize the morphology of the self-assembled peptides. As is shown in Figure 1a-c and Figures S1a-b, the Fmoc-FWH tripeptide self-assembled into highly uniform right-handed helical nanofibers with a statistical width of 42±7 nm and a statistical helical pitch of 180±13 nm (Figures S2). Surprisingly, when the middle amino acid Trp (W) was replaced by Phe (F), the twisted fibrils formed by Fmoc-FFH were exclusively left-handed contrary to the right handedness of the nanohelices self-assembled by Fmoc-FWH (Figure 1d-f and Figure S1c-d). These helices have a width of 40±2 nm and a helical pitch of 102±9 nm (Figures S2). Moreover, the AFM image of the left-handed Fmoc-FFH nanohelices showed some helical nanofibers intertwined with each other, forming a superhelical structure (Figure S1d). This structure has some similarities to that observed by Xie et al., in which the two individual helices intertwined to form a double helix.48 This pair of designed tripeptides, differing only at the aromatic side chain of the middle amino acids, self-assembled into nanofibers with the opposite handedness. The results indicated the crucial role of the amino acid sequence of the designed peptides in determining the handedness of the self-assembled structures. Given the effect of pH on the self-assembled nanostructures, we also investigated the morphologies of the fibrils at pH 3.0 and pH 9.0. However, the morphologies of Fmoc-FWH and Fmoc-FFH displayed the cylinder fibrils without macroscopic handedness, probably due to the change of terminal charges driven by pH variation (Figure S3). Because the theoretical pKa of His is 6, the peptides at pH 6 were expected to be present in 7


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both protonated and deprotonated form almost in equal amounts. Conversely, protonated or deprotonated histidine was abundantly present at pH 3 or pH 9, respectively.

Figure 1. (a) SEM, (b) AFM and (c) TEM of the Fmoc-FWH right-handed helical nanofibers formed at pH 6. (d) SEM, (e) AFM and (f) TEM images of the Fmoc-FFH left-handed helical nanofibers formed at pH 6.

Circular dichroism (CD) spectroscopy was employed to analyze the secondary structures of peptide nanohelices with different handedness. As is shown in Figure 2a, the CD spectra of the Fmoc-FWH peptide solution exhibits a positive Cotton effect at 195 nm and two negative Cotton effect at 204 nm and 215 nm, indicating the formation of atypical twisted β-sheet structures.54 The additional peak at 204 nm may arise from π−π stacking of the aromatic side chains in the helical nanofibers or the distortion of the β-sheets, which was also observed in previous studies.55-57 Moreover, the spectra displays a positive Cotton effect with three positive peaks at 285 nm, 293 nm and 305 nm, which characterizes the asymmetric helical arrangements through π– 8


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π interactions formed by the Phe and Trp residues and the fluorenyl groups.48, 58 On the other hand, the Fmoc-FFH peptide solution shows a maximum at 193 nm, a minimum at 220 nm as well as a weak negative peak at 204 nm in the CD spectra, indicating the nonclassical β-sheet structures similar to the Fmoc-FWH (Figure 2b). Consistently, the three negative peaks at 285 nm, 294 nm and 303 nm provided evidence that the aromatic side chain and the fluorenyl groups of Fmoc-FFH existed in an asymmetric environment. The right- or left-handed nanohelices formed by the Fmoc-FWH and Fmoc-FFH, respectively, showed similar chiroptics in the peptide adsoption region, but exhibited nearly opposite CD cotton effects in the aromatic regions. Combining the results of SEM and AFM, we speculated that the handedness of the nanohelices might be determined by the non-covalent interactions between the aromatic side chains of the peptides. Fourier transform infrared spectroscopy (FTIR) revealed that both of the right-handed Fmoc-FWH nanohelices and left-handedness Fmoc-FFH nanohelices had adsorption peaks at 1635 cm−1 (Figure S4), indicating the formation of β-sheet secondary structures.29,

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The in situ synchrotron wide angle

X-ray diffraction (WAXD) were used to probe the molecular packing of the assembles. The Fmoc-FWH and Fmoc-FFH peptides produced scattering peaks at 12.9 and 13.1 nm-1, corresponding to spacings of 4.86 and 4.79 Å, respectively (Figure S5), which could be attributed to the β-sheet conformation.40 Consistently, the Bragg peaks at 2θ = 2.76° were observed in the XRD patterns for right-handed Fmoc-FWH helical nanofibers (Figure 2c), corresponding to the d-spacing of 3.19 nm which was equal to the length of two molecules approximately (Figure S6a). 9


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Therefore, we speculate that four parallel stacks of Fmoc-FWH molecules were connected with a twofold rotation axis (Figure S6b), which was reminiscent of the single crystal structure of Fmoc-FF reported by Adams et al.60 However, there was no Bragg peaks detected in the XRD spectra of Fmoc-FFH nanostructures, which might arise from the highly helical twisting of the nanofibers that decrease the crystallinity of the materials (Figure 2d).38

Figure 2. (a-b) CD spectra and (c-d) 2D X-ray diffraction patterns of the Fmoc-FWH and Fmoc-FFH assemblies formed at pH 6.

Molecular Dynamics Simulations were performed to assess the handedness tendency within the self-assembled Fmoc-FFH and Fmoc-FWH helical nanofibers. Two models were constructed as the initial conformation based on the results of CD, FTIR, SAXS and XRD analysis. Four β-sheets composed of 48 Fmoc-FFH peptides were collocated in the M1 model and Fmoc-FWH in M2 model, respectively (Figure S7). In the model, the four β-sheets were related by a double rotation axis and in each β-sheet the Fmoc-FFH and Fmoc-FWH molecules were both oriented parallel to each 10


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other. The carboxyl group and imidazole group of histidine residues are both ionized at pH 6 based on the pKa of the two peptides (Figure S8), indicating the existence of electrostatic interactions among the peptides. The simulation results showed that the M1 and M2 models would rotate spontaneously into left-handed and right-handed twists, respectively, after 40 ns calculations (Figure 3). The Root Mean Square Deviation (RMSD) value of each system was plotted against simulation time (Figure S9). RMSD of both systems stayed nearly constant after 20 ns, indicating the system was stabilized. The Fmoc-FFH β-sheet assemblies tended to form left-handed helical fibers. However, the Fmoc-FWH twisted in right-handed orientation, which might be partly due to the steric hindrance of the bulky side chain of tryptophan. Further analysis of noncovalent interactions between peptides was performed using the RDG method61 by Multiwfn v3.6.62 Figure 4a and b showed that π-π stacking interactions and steric hindrance exist between the side chain of two adjacent molecules. The five-member ring and the phenyl ring of the indole side chain constituted a bigger steric barrier so that the peptide had a tendency to form a local right-handed secondary structure, leading to the formation of right-handed helical nanostructures.

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Figure 3. (a) Molecular dynamic simulations of Fmoc-FFH self-assembling into left-handed helical fibers and (b) Fmoc-FWH self-assembling into right-handed helical fibers.

Moreover, number of hydrogen bonds during the simulation period was analyzed (Figure S10). The system of Fmoc-FFH stabilized rapidly while that of the Fmoc-FWH was slower, which was consistent with the changing profile of hydrogen bond. Thus, it could be inferred that the formation of hydrogen bond was another important factor in the formation of helical nanostructures. The number of hydrogen bonds between Fmoc-FWH and water was about 450, much higher than that of the Fmoc-FFH (~400). A possible explanation was that the side chain of tryptophan in Fmoc-FWH contains a nitrogen atom that could form hydrogen bonds with water (Figure 4c and 4d). The stronger hydrogen bonding interactions had a vital effect on the handedness during the self-assembly of Fmoc-FWH, leading to the formation of right-handed helical fibers. Furthermore, solvent accessible surface area (SASA) was calculated as shown in Figure S11. SASA of Fmoc-FFH (~170) was less than that of Fmoc-FWH (~180), primarily reflected in difference of hydrophilic area, which was caused by the existence of tryptophan. These results provide evidence that the local electrostatic interactions, π–π stacking, steric hindrance and hydrogen bonds could determine the torsional direction of the β-sheets, leading to the self-assembly of peptide nanofibers with opposite handedness without changing the chirality of the constituent amino acids.

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Figure 4. π-π interactions and steric hindrance between two adjacent peptides of a) Fmoc-FFH and b) Fmoc-FWH. The green part represents π-π interactions and the dark yellow part represents steric hindrance (as the black arrow pointed to). Hydrogen bonds formed during the self-assembly of c) Fmoc-FFH and d) Fmoc-FWH. The nitrogen atom of tryptophan in Fmoc-FWH forms an extra hydrogen bond with a water molecule (as the red arrow indicated).

To validate the universality of the side chain on the chiral self-assembly of the peptides, we further investigated the self-assembly of another four pairs of Fmoc-tripeptides, i.e., Fmoc-FWR and Fmoc-FFR, Fmoc-FWE and Fmoc-FFE, Fmoc-FWD and Fmoc-FFD, Fmoc-FWS and Fmoc-FFS. They differ in the terminal amino acid with different terminal charges. SEM images and CD spectrum revealed that the four pairs of peptides, bearing FW or FF sequence, self-assembled into nanofibers with opposite handedness at the identical self-assembling conditions (Figure 5, Figure S12). As is shown in Figure 5a and Figure S13a, the Fmoc-FWE was found to self-assemble into well-defined right-handed helices. The self-assembled nanohelices were highly homogeneous and had diameters of ∼24 nm, helical pitches of ∼65 nm and lengths up to hundreds of micrometers (Figure S14). However, the Fmoc-FFE self-assembled into very thin nanofibers without microscopic helical 13


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structures (Figure 5b and Figure S13b) and had a diameter of ∼8 nm (Figure S14). Correspondingly, the SEM images (Figure 5c and Figure S13c) confirmed that the Fmoc-FWS self-assembled into right-handed twisted nanofibers with an average diameter of 33 nm and helical pitch of ~135 nm (Figure S14). While the Fmoc-FFS self-assembled into left-handed helical nanoribbons with a width of ∼29 nm and a helical pitch of 119 nm (Figure 5d, Figure S13d and Figure S14). CD analysis revealed that both of the Fmoc-FWE and Fmoc-FFE nanofibers had a typical cotton effect with a maximum at 192 nm and a minimum at 215-217 nm, which could be associated with the β-sheet secondary structures (Figure 5e). However, the two peptides showed approximately opposite exciton−couplet Cotton effect in the aromatic region with two positive peaks at 274 nm, 302 nm for Fmoc-FWE and 264 nm, 302 nm for Fmoc-FFE, respectively. This indicated that the Fmoc-FWE and Fmoc-FFE showed opposite chiral interactions between the aromatic rings of the amino acid side chain and Fmoc groups. Similarly, despite the slight variation in the adsorption peaks and intensity, the self-assembled Fmoc-FWS and Fmoc-FFS nanofibers also showed opposite cotton effects in the aromatic region (Figure 5f). The peak shifts of the Fmoc-tripeptide were ascribed to a possible distortion of the β-sheets or varied packing modes.39, 63

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Figure 5. SEM images of the self-assembled nanofibers formed at pH 6. (a) Fmoc-FWE, (b) Fmoc-FFE, (c) Fmoc-FWS, (d) Fmoc-FFS. CD spectra of (e) Fmoc-FWE and Fmoc-FFE, (f) Fmoc-FWS and Fmoc-FFS.

Combining the results for the self-assembly of the five pairs of the Fmoc-tripeptides, the Fmoc-FWX (X = H, R, S, E or D) trend to form right-handed helices nanostructures while Fmoc-FFX (X = H, R, S, E or D) trend to form left-handed helices nanostructures. These results demonstrated that the side chain patterning in short peptides is of vital importance in determining the handedness of the self-assembled helical nanofibers (Scheme 1). In general, the self-assembly of the peptide nanostructures may be driven by a synergistic interplay of various non-covalent interactions, including hydrogen bonding, electrostatic interactions and aromatic stacking. It has been shown that the handedness of the chiral self-assembly was mainly dictated by the constituent amino acid chirality and the electrostatic interactions between the charges of terminal residues or side chains.41 However, for the study reported herein, the side chain interactions (hydrogen bonding, π-π stacking 15


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and the steric effects) in the peptides bearing all L-amino acids caused the β-sheets to twist in different orientation, leading to the formation of chiral nanostructures with opposite handedness. Furthermore, it is worth noting that the diameters of the nanofibers from self-assembly of the Fmoc-tripeptides varied with the substitutable terminal amino acid (Scheme 2). We measured the pKa of Fmoc-FWH and Fmoc-FFH at different concentrations. As shown in Figure S8, both of the two peptide showed an apparent pKa at pH 7-8, this value is higher than the theoretical pKa for amidazole group on His, which might be attributed to the self-assembly of the peptides.64 According to the pKa of the Fmoc-FWH and Fmoc-FFH (Figure S8), the two peptides should be zwitterionic because a significant portion of the carboxyl and imidazole groups are ionized at pH 6. Similarly, the Fmoc-FWR and Fmoc-FFR should be zwitterionic as well, because the high pKa (12.48) of guanidio group at the side chain of the Arg. Correspondingly, the Fmoc-FWS and Fmoc-FFS could be deprotonated and each molecule carried one negative charge. While the Fmoc-FWE and Fmoc-FFE or Fmoc-FWD and Fmoc-FFD bear two negative charges when most of the terminal carboxyl groups are deprotonated at pH 6. Zeta potential measurement demonstrated that the surface net charges of the peptide assemblages enhanced with the increase of peptide terminal charges (Figure S15). For the self-assembly of Fmoc-FWH and Fmoc-FFH or Fmoc-FWR and Fmoc-FFR, electrostatic attractions between positive and negative charges of terminal residues lead monomers much more easily to aggregate between β-sheets,23, 65, 66 thus giving rise to larger width of helix nanofibers. 16


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As for Fmoc-FWS and Fmoc-FFS, the reduced fibril diameters could be attributed to the electrostatic repulsion of the terminal charges. While much stronger electrostatic repulsion between Fmoc-FWE, Fmoc-FFE, Fmoc-FWD or Fmoc-FFD with increasing negative terminal charges limit the stacking of the assembled monomers, leading to the formation of much narrower nanohelices (Figure S16). The statistical significance between the length of Fmoc-FWH, Fmoc-FWR, Fmoc-FWS, Fmoc-FWE and Fmoc-FWD or Fmoc-FFH, Fmoc-FFR, Fmoc-FFS, Fmoc-FFE and Fmoc-FFD has been calculated. The results are in Table S1 and Table S2. In particular, the handedness of the Fmoc-FFE assemblages was even beyond the resolution of our SEM and TEM facilities (Figure 5b, Figure S13b). These results clearly indicated that the electrostatic repulsions at the terminal amino acids played a crucial role in determining the chiral expression and the width of the self-assembled nanofibers.

Scheme 2. Schematic illustration showing the relationship between electrostatic interactions and fibers diameters based on the self-assembly of the five pairs of the tripeptides.

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CONCLUSION The amino acid sequence pattern of short peptides exerted a profound effect on the chirality of the self-assembled materials. We tested the chiral self-assembly of five pairs of tripeptides composed of different amino acids. The Fmoc-FWX (X = H, R, S, E or D) trend to form right-handed helices nanostructures while the Fmoc-FFX (X = H, R, S, E or D) trend to form left-handed helices nanostructures. The handedness of helical nanofibers was dictated by the aromatic side chains at the middle amino acid residues owing to the π–π stacking, steric effects and the related hydrogen bonding interactions. Moreover, the width of the nanofibers indicating the scale of chiral amplification was determined by the charges of the terminal amino acid. These findings provide insights into the chiral self-assembly of peptides, which could be utilized for the rational design of chiral nanostructures with precisely controlled architectures and functions.

EXPERIMENTAL SECTION Chemicals

and

Materials:

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-tryptophan-L-histidine (Fmoc-FWH,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-phenylalanine-L-histidine (Fmoc-FFH,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-tryptophan-L-arginine 18


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(Fmoc-FWR,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-phenylalanine-L-arginine (Fmoc-FFR,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-tryptophan-L-glutamic (Fmoc-FWE,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-phenylalanine-L-glutamic (Fmoc-FFE,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-tryptophan-L-aspartic (Fmoc-FWD,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-phenylalanine-L-aspartic (Fmoc-FFD,

>98%),

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-tryptophan-L-serine (Fmoc-FWS, >98%)

and

N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-L-phenylalanine-L-serine (Fmoc-FFS, >98%) was synthesized from GL Biochem Ltd (Shanghai, China). The HPLC and MS spectra data provide by GL Biochem Ltd are in the supporting information (Figure S17, Figure S18). Sodium hydroxide and hydrochloric acid were purchased from Sigma-Aldrich (Shanghai, China). Preparation of Fmoc-tripeptide Chiral Nanostructures: In a typical experiment, the lyophilized Fmoc-FWH powder (2 mmol, 1.42 mg) was dissolved in an aqueous solution (950 μL) under stirring at room temperature through the addition of an appropriate amount of 0.5 M NaOH (50 μL). Then, 0.1 M HCl was added to the 19


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mixture solutions and adjusted to pH 6. Afterward, an appropriate amount of ddH2O was added to the solutions to a final concentration of 2 mM. The samples were then incubated at 25 °C for 24 h without any disturbance. For the other Fmoc-tripeptide, the peptide assemblies were obtained following the similar preparation procedure of Fmoc-FWH as described above. However, because the Fmoc-FWR and Fmoc-FFR did not dissolve in H2O by adding HCl and NaOH, we investigated the self-assembly of Fmoc-FWR and Fmoc-FFR in a 5:95 (v/v) methanol/H2O mixture. The peptides were firstly dissolved in methanol at a concentration of 100 mM, which was then diluted in 950 μL phosphate buffer at pH 6. Scanning Electron Microscopy: The morphologies and structures of the Fmoc-tripeptide assemblies were investigated using scanning electron microscopy (SEM, Hitachi S-4800, Japan) at an acceleration voltage of 3 or 5 kV. To prepare the samples, the Fmoc-tripeptide assemblies were spun on glass plates to dry and sputter-coated with platinum using an E1045 Pt-coater (Hitachi High-technologies Co., Japan). Atomic Force Microscopy: For further observation, we used atomic force microscopy (AFM, afm5500, American) to characterize the assemblies. The samples (20 μL) for AFM measurement was spread on a mica surface and air dried before observation. Transmission Electron Microscopy: The samples for the TEM analysis were prepared as follows: the assemblies were dispersed into ddH2O and then 10 μL aliquots of the dispersion were spread onto a 300-mesh carbon-coated copper grid. 20


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After air-drying, the samples were negatively stained with 1 wt% phosphotungstic acid solution for 2 min. Circular Dichroism: Circular dichroism (CD) analysis was employed on a J-810 CD spectropolarimeter (Jasco Inc., Japan). The spectra were collected over a wavelength range of 185-350 nm. The data were recorded with a scanning speed of 500 nm min−1 with bandwidth of 0.2 nm. Fourier Transform Infrared Spectroscopy: Fourier transform infrared (FTIR) spectroscopy was recorded on a Nicolet-560 FTIR spectrometer (Nicolet Co., USA) across the range of 400-4000 cm-1 at room temperature. The peptides were dissolved in D2O to eliminate the interference of H2O. The samples were adjusted to pD value to 6 with diluted NaOH and HCl in D2O. X-ray

Scattering

Measurements:

Small-angle

X-ray

diffraction

(XRD)

measurements were performed using a PANalytical/X’Pert PRO MPD system with a Cu/Kα radiation source (λ = 1.5406 Å) for small angle diffraction (0.5°–5°) with a scanning speed of 0.5° min−1. In situ X-ray scattering measurements were carried out at beamline 1W2A of the Beijing Synchrotron Radiation Facility (Beijing, China). Mar165-CCD was set at 151 mm sample–detector distance. The wavelength of the radiation source was λ = 1.54 Å. pH Titration: Fmoc-FWH and Fmoc-FFH peptides were dissolved in ddH2O by adding 0.5 M NaOH at a concentration of 0.5, 2, 5 or 10 mmol L−1 at pH≈12. The titration curves were measured by monitoring the pH values during the stepwise

21


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addition of 0.1 M HCl. The tripeptides samples were stirred during the titration process. Zeta Potential Measurement: Zeta potential measurements of these Fmoc-tripeptide assemblies were investigated using a Zetasizer Nano-ZS (Malvern Instruments Ltd., U.K.). The samples of the assemblies were synthesized as mentioned before at pH 6. Molecular Dynamics Simulation: Molecular Dynamics Simulations (MDSs) were performed using the Gromacs program67, 68 and the Amber99SB-ILDN force field.69 Initial molecular structures of Fmoc-FFH and Fmoc-FWH were constructed using Accelrys Materials Studio 2.5 software. The tLeaP tool was used to add the hydrogen atom of the Fmoc-tripeptide residue. Models was centered in an orthorhombic periodic boundary condition (PBC) box with a margin of 1 nm and filled with SPCE water molecules.70 Na+ and Cl- ions were added to make the system electrically neutral. The system was performed with 5000 steepest descent steps and 5000 conjugate gradient minimization steps to achieve energy minimization and then simulated for 40 ns at a time step of 1 fs in the NPT ensemble at a temperature of 300K. Nonbonded and long-range electrostatic interactions were calculated using the Particle Mesh Ewald (PME) method 71 with a cut-off value of 1.0 nm. The MD traces were further analyzed using Gromacs analysis tools and VMD.72 ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21621004, 21476165, 21606166, and 51773149), the Beiyang Young Scholar of

22


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Tianjin University (2012), and the State Key Laboratory of Chemical Engineering (SKL-ChE-08B01). The authors thank Prof. Zhonghua Wu and Dr. Guang Mo of Beijing Synchrotron Radiation Facility (Beijing, China) for assistance with the X-ray scattering measurement. Q.X. appreciates Chen Cheng for her assistance in the experiment. SUPPORTING INFORMATION Supplementary SEM, AFM and TEM images, scale statistical data, peptide spectroscopic data, Synchrotron WAXS data, peptide pKa data, Molecular Dynamics Simulations additional data and peptide Zeta potential data. This material is available free of charge via the Internet at http://pubs.acs.org. REFERENCES 1.

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Aromatic Motifs Dictate Nanohelix Handedness of Tripeptides - ACS

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