Study on the self-assembly of aromatic antimicrobial peptides based on different PAF26 peptide sequences

Fengyi Cao; Genxing Zhu; Meng Song; Xiaoli Zhao; Gangqing Ma; Mengqing Zhang

doi:10.1515/epoly-2022-0012

Article Open Access

Study on the self-assembly of aromatic antimicrobial peptides based on different PAF26 peptide sequences

Fengyi Cao , Genxing Zhu , Meng Song , Xiaoli Zhao , Gangqing Ma and Mengqing Zhang

Published/Copyright: March 16, 2022

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From the journal e-Polymers Volume 22 Issue 1

Abstract

Antimicrobial peptide (AMP) self-assembly is an effective way to synthesis antimicrobial biomaterials. In previous studies, we found PAF26 AMP (Ac-RKKWFW-NH₂) and its derivative K₂–F₂ peptide (Ac-KKRKKWFWFF-NH₂) could both self-assemble into hydrogels, but they had distinct microscopic structures. Therefore, in this work five PAF26 peptide derivatives with different numbers of aromatic amino acids are designed to better understand the self-assembly mechanism of aromatic AMP. The transmission electron microscopy, infrared spectroscopy, circular dichroism, and fluorescence spectroscopy characterizations are carried out to study the microscope structure, secondary conformation, and molecular interactions. It is found that the five peptide derivatives have different microscopic structures, and the number of aromatic amino acids will affect the peptide hydrogen bonding and aromatic stacking interactions, causing significant differences in the secondary conformation and microscopic structure. This work will enhance the comprehension of aromatic AMP self-assembly.

Keywords: antimicrobial peptide; self-assembly; microscopic structure; secondary conformation; molecular interaction

1 Introduction

Antimicrobial peptides (AMPs), due to their broad-spectrum antibacterial ability and low bacterial resistance, are emerging as promising antibiotic substitutes, and by now several AMPs have been commercially used in clinic (1). However, there are still some challenges that hinder the applications of AMPs, such as weak bioactivity, immature stability, and high toxicity (2). In recent years, several strategies have been developed to deal with these problems, for example combining AMPs with metal materials to enhance the antimicrobial effect (3), self-assembling AMPs to improve the stability and activity (4,5), developing environment responsive AMPs to reduce the toxicity (6), and so on (7,8). Among them, the self-assembling method shows outstanding advantages (9).

Peptide self-assembly is a spontaneous process that mainly depends on the weak non-covalent molecular interactions including hydrogen bonding interaction, electrostatic interaction, aromatic stacking interaction, and hydrophobic interaction (10). Through self-assembly, peptides could change their conformations and aggregate into a variety of nanostructures including micelles (11), fibers (12), ribbons (13), and tubes (14) under mild conditions, which could be widely used for drug delivery and tissue engineering (15,16). In the past decades, a lot of studies have been reported to control the peptides self-assembly (17,18,19,20), and these achievements gave excellent referees for AMP self-assembly.

AMP is a special kind of peptide that has amphiphile structure, which gives it the potential to self-assemble in water. Despite using native AMP, the peptide sequence could be artificially modified to enhance the self-assembly possibility (21,22). Lombardi et al. (5) designed an AMP amphiphile WMR PA by linking native antibacterial WMR peptide with a peptide segment of aliphatic residues (AAAAAAA) containing a lipidic tail (C₁₉H₃₈O₂). It was found that the WMR PA peptide could self-assemble into stable nanofibers, inhibit biofilm formation, and eradicate the already formed biofilms. Liu et al. (23) designed and synthesized an amphiphilic peptide CG3R6TAT containing hydrophobic cholesterol (C) and hydrophilic R6TAT peptide sequence. This peptide could self-assemble into core-shell structured nanoparticles, which could strongly enhance its antimicrobial activity. But one question is that with different molecular designs, the nanoarchitectures of AMPs are distinct.

In our previous works, we found that though PAF26 AMP (Ac-RKKWFW-NH₂) and its derivative K₂–F₂ peptide (Ac-KKRKKWFWFF-NH₂) both could self-assemble into hydrogels, they had distinct microscopic structures: one tended to self-assemble into nanoparticles, and the other tended to self-assemble into nanofibers (24,25). Therefore, to better understand the self-assembly mechanism of aromatic AMP, five PAF26 AMP derivatives were designed. As shown in Table 1, we divided the five peptides into two groups: In group I, the peptides had the same hydrophilic KRKK peptide sequence and different numbers of aromatic amino acids; In group II, the peptides had the same hydrophilic KKRKK peptide sequence and different numbers of aromatic amino acids. In addition, the chemical structure of each peptide is shown in Scheme 1.

Table 1

Peptide sequence and molecular weight of each designed peptide

Group	Abbreviation	Peptide sequence	Molecular weight (g·mol⁻¹)
Group I	KRW6	Ac-KRKKWFW-NH₂	1,119.36
	KRW6-F	Ac-KRKKWFWF-NH₂	1266.54
	KRW6-FF	Ac-KRKKWFWFF-NH₂	1413.71
Group IIa	KKRW6	Ac-KKRKKWFW-NH₂	1247.54
Group IIa	KKRW6-F	Ac-KKRKKWFWF-NH₂	1394.71

a
The Ac-KKRKKWFWFF-NH₂ peptide has already been studied in a previous report (25).

Scheme 1

The chemical structures of KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptides.

2 Materials and methods

2.1 Materials

Five PAF26 peptide derivatives: KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptides (purity ≥95%) were purchased from Shanghai GL Biochem Ltd (Shanghai, China). Sodium hydroxide (AR) and hydrochloric acid (37 wt%) were purchased from Sinopharm chemical reagent Co., Ltd (Shanghai, China). Potassium bromide (SP) was purchased from Shanghai Yi En chemical technology Co., Ltd (Shanghai, China). Thioflavin T (ThT) was purchased from Aladdin Biochemical Technology Co., Ltd (Shanghai, China). All the materials were used as received.

2.2 AMP self-assembly experiments

40 mg KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide was dissolved in 1 mL of distilled water separately and then the pH value of each peptide solution was adjusted to 3 using diluted hydrochloric acid solution. To trigger peptide self-assembly, 0.5 mol·L⁻¹ diluted sodium hydroxide solution was added into each peptide solution slowly. The addition of sodium hydroxide solution was stopped when the peptide solution was observed to lose flowability, and the solution was kept overnight to let it self-assemble completely.

2.3 Transmission electron microscopy (TEM)

To study the microscopic structures of KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide self-assemblies, the self-assemblies were diluted ten times and immediately dropped on ultra-thin carbon films, air dried, and observed under a TEM (JEOL JEM 2100Plus, Japan).

2.4 Fourier transform infrared spectroscopy (FTIR)

To study the secondary conformation and hydrogen bonding interactions of KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide self-assemblies, the self-assemblies were frozen in liquid nitrogen and lyophilized using a freeze-dryer (LGJ-10, China). Then, each sample was mixed with potassium bromide, ground, and repressed into piece. The FTIR spectra were recorded on a spectrophotometer (Nicolet iS50, USA).

2.5 Circular dichroism (CD)

The circular dichroism information of KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide self-assemblies was studied using a solid spectropolarimeter (JASCO J-815, Japan) with the wavelength ranging from 190 to 280 nm.

2.6 Fluorescence spectroscopy

To evaluate the aromatic stacking interactions during the peptide self-assembly, the fluorescence spectra of KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide solutions at pH 3, and KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide self-assemblies were detected on a fluorescence spectrophotometer (F-7100, Japan). λ _ex = 310 nm and λ _em = 330–600 nm.

2.7 ThT fluorescence assay

The ThT working solution was prepared by dissolving 4 mg ThT into 4 mL of distilled water and filtered through a 0.2 μm syringe filter. In each 0.5 mL of KRW6, KRW6-F, KRW6-FF, KKRW6, or KKRW6-F peptide self-assembly, 0.5 mL of ThT working solution was added and mixed, then each mixed solution was kept in room temperature for 5 min to allow ThT to bind with the peptide assembly. At last, the fluorescence excitation spectra of ThT working solution and KRW6, KRW6-F, KRW6-FF, KKRW6, and KKRW6-F peptide mixed solutions were measured in the range of 300–455 nm with the emission wavelength of 482 nm, and the fluorescence excitation spectra were measured in the range of 465–700 nm with the excitation wavelength of 450 nm.

3 Results and discussion

3.1 Microscopic structure of KRW6, KRW6-F, and KRW6-FF peptide self-assemblies

Peptide self-assembly is a process in which peptide molecules aggregate together under the force of weak molecular interactions, and the microscopic structure of self-assembly is always different with distinct molecular sequence and molecular interactions. As shown in Figure 1, KRW6 peptide was self-assembled into long nanofibers with pronounced twisting structures; KRW6-F peptide was self-assembled into mixed nanofibers and small nanoparticles; KRW6-FF peptide was self-assembled into nanofibers with seldom twisting structures. In addition, it was seen that the microscopic structures of KRW6 and KRW6-FF peptides were more regular than that of KRW6-F peptide.

Figure 1

TEM images of (a1 and a2) KRW6, (b1 and b2) KRW6-F, and (c1 and c2) KRW6-FF peptide self-assemblies. Scale bars: (a1–c1) 200 nm and (a2–c2) 100 nm.

3.2 Self-assembly mechanism of KRW6, KRW6-F, and KRW6-FF peptides

The microscopic structure of peptide self-assembly is always related to peptide secondary conformation. And the FTIR absorptions in the amide I region could give information about the secondary conformation of peptide self-assemblies (26). As shown in Figure 2a, KRW6, KRW6-F, and KRW6-FF peptides showed strong absorptions at around 1,630–1,632 cm⁻¹, which were the characteristic feature of β-sheet conformation (27). And the absorptions at around 1,677–1,681 cm⁻¹ showed that they might adopt antiparallel β-sheet conformation or β-turn conformation (28,29). In addition, as shown in the solid circular dichroism spectra (Figure 2b), KRW6 peptide exhibited a broad negative peak at 215 nm (nπ* transition), suggesting that it adopted β-sheet conformation (30). KRW6-F peptide exhibited a negative peak at 200 nm (ππ* transition), showing that it adopted random coil conformation. And it also showed less pronounced peaks at 213 and 238 nm (nπ* transition), indicating that it also contained β-sheet and β-turn conformations (31). Similar to KRW6-F peptide, KRW6-FF peptide exhibited a negative peak at 200 nm (ππ* transition), and its peak at 236 nm (nπ* transition) was much stronger than that of KRW6-F peptide, demonstrating that it contained larger number of β-turn conformations. ThT is a popular fluorescent dye for detecting protein or peptide aggregate with amyloid fibril structure, and it was reported that β-sheet structure could cause large enhancement in ThT fluorescence (32,33). In Figure 2c, it was shown that new excitation peaks (λ _em = 482 nm) at around 450 nm were displayed for KRW6, KRW6-F, and KRW6-FF peptides. And compared with ThT solution, the fluorescence emission intensity (λ _ex = 450 nm) of KRW6 peptide at 494 nm, KRW6-F peptide at 504 nm, and KRW6-FF peptide at 501 nm were strongly increased (Figure 2d) and the maximum fluorescence intensity of KRW6-F peptide was much higher than that of KRW6 and KRW6-FF peptides. These results indicated that there were β-sheet structures in KRW6, KRW6-F, and KRW6-FF peptide self-assemblies, and KRW6-F peptide had more β-sheet structures than KRW6 and KRW6-FF peptides (33,34).

Figure 2

(a) FTIR and (b) CD spectra of KRW6, KRW6-F, and KRW6-FF peptide self-assemblies; (c) fluorescence excitation spectra and (d) fluorescence emission of ThT solution (1 mg·mL⁻¹) and KRW6, KRW6-F, and KRW6-FF peptide self-assemblies dyed with ThT with λ _em = 482 nm and λ _ex = 450 nm, respectively.

The FTIR absorptions in the amide A band region could be applied to distinguish the intermolecular and intramolecular hydrogen bonding interactions in the self-assembly (35,36). As shown in Figure 2a, the amide A band absorption of KRW6 peptide was about 3,300 cm⁻¹, showing that KRW6 peptide had more possibility of adopting intramolecular hydrogen bonding interaction in the self-assembly. For KRW6-F and KRW6-FF peptides, the amide A band absorptions were 3,285 and 3,277 cm⁻¹ (below 3,300 cm⁻¹), showing that the self-assemblies were dominated by intermolecular hydrogen bonding interactions (37). In addition, the absorption of KRW6-FF peptide was lower than that of KRW6-F peptide, probably demonstrating that the intermolecular hydrogen bonding interaction of KRW6-FF peptide was stronger than that of KRW6-F peptide.

For aromatic peptides, the aromatic stacking interactions could be investigated by fluorescence emission spectroscopy. As shown in Figure 3, the emission spectra of peptide solutions and self-assemblies were measured. The emission maximum of KRW6 peptide after self-assembly was red-shifted from 362 to 396 nm; KRW6-F peptide after self-assembly was red-shifted from 366 to 417 nm; KRW6-FF peptide after self-assembly was red-shifted from 356 to 400 nm and 414 nm. The red-shifting of KRW6-F and KRW6-FF peptide was bigger than that of KRW6 peptide, showing that the aromatic stacking interactions in KRW6-F and KRW6-FF peptide self-assemblies were stronger than that of KRW6 peptide self-assembly. In addition, all the three peptide self-assemblies showed excimer emission peak at around 477 nm, which was the extended aggregation of aromatic motifs.

Figure 3

Fluorescence spectra of KRW6, KRW6-F, and KRW6-FF peptide solutions (40 mg·mL⁻¹, pH = 3) and peptide self-assemblies.

3.3 Microscopic structure of KKRW6 and KKRW6-F peptide self-assemblies

The microscopic structures of KKRW6 and KKRW6-F peptide self-assemblies are shown in Figure 4. It was shown that KKRW6 peptide was self-assembled into short nanofibers, mixed with some irregular structures; KKRW6-F peptide was self-assembled into long nanofibers with some twisting structures, and there were also some nanoparticles and irregular structures.

Figure 4

TEM images of (a1 and a2) KKRW6 and (b1 and b2) KKRW6-F peptide self-assemblies. Scale bars: (a1 and b1) 200 nm and (a2 and b2) 100 nm.

3.4 Self-assembly mechanism of KKRW6 and KKRW6-F peptides

As shown in the FTIR spectra (Figure 5a), in the amide I region, KKRW6 and KKRW6-F peptides had strong absorptions at around 1,630–1,631 cm⁻¹, showing that they adopted β-sheet conformation. And the absorptions at 1,682 cm⁻¹ confirmed that they might adopt antiparallel β-sheet conformation or β-turn conformation. In the solid circular dichroism spectra (Figure 5b), KKRW6 peptide exhibited a broad negative peak at 216 nm (nπ* transition), suggesting that it adopted β-sheet conformation. Besides, the negative peak at 200 nm (ππ* transition) showed that it also contained a number of random coil conformation. KKRW6-F peptide showed a negative peak at 200 nm (ππ* transition), demonstrating the existence of random coil conformation. Besides, the positive peak at 208 nm (ππ* transition) and less pronounced peaks at 211 and 255 nm (nπ* transition), indicated that it also contained β-sheet and β-turn conformations (16,31). From the ThT fluorescence excitation spectra (Figure 5c), it was shown that new excitation peaks (λ _em = 482 nm) at around 445 nm were displayed for KKRW6 and KKRW6-F peptides. And compared with ThT solution, the fluorescence emission intensity (λ _ex = 450 nm) of KKRW6 peptide at 487 nm and KKRW6-F peptide at 503 nm were strongly increased (Figure 5d). These results indicated that there were β-sheet structures in KKRW6 and KKRW6-F peptide self-assemblies. Besides, the maximum fluorescence intensity of KKRW6 peptide was much higher than that of KKRW6-F peptide, showing that KKRW6 peptide had more β-sheet structures than KKRW6-F peptide.

Figure 5

(a) FTIR and (b) CD spectra of KKWR6 and KKWR6-F peptide self-assemblies; (c) fluorescence excitation spectra and (d) fluorescence emission of ThT solution (1 mg·mL⁻¹) and KKWR6 and KKWR6-F peptide self-assemblies dyed with ThT with λ _em = 482 nm and λ _ex = 450 nm, respectively.

Besides, the amide A band absorption of KKRW6 peptide was about 3,305 cm⁻¹, showing that it had more probability to self-assemble through intramolecular hydrogen bonding interaction. For KKRW6-F peptide, the absorption was 3,288 cm⁻¹ (below 3,300 cm⁻¹), showing that the self-assembly was dominated by intermolecular hydrogen bonding interaction.

The fluorescence emission spectra of KKRW6 and KKRW6-F peptide solutions and self-assemblies are shown in Figure 6. The emission maximum of KKRW6 peptide after self-assembly was red-shifted from 364 to 424 nm, and KKRW6-F peptide after self-assembly was red-shifted from 362 to 412 nm, suggesting that both of them had efficient aromatic overlaps. In addition, it was found that both of them showed excimer emission peak at around 469 nm, which was the extended aggregation of aromatic motifs.

Figure 6

Fluorescence spectra of KKRW6 and KKRW6-F peptide solutions (40 mg·mL⁻¹, pH = 3) and peptide self-assemblies.

Aromatic AMP belongs to a special kind of peptide that is always called aromatic peptide amphiphile, due to its special amphiphile structure and sufficient aromatic motifs. In aromatic peptide amphiphile self-assembly systems, the aromatic motifs played an extremely important role that they were more likely to form nanofibers, nanoribbons, or nanotubes through stacking arrangements (38–43). In this work, comparing KRW6 peptide with KRW6-F and KRW6-FF peptides, we could find that the peptides with larger number of aromatic amino acids had stronger aromatic stacking interaction. In addition, the stronger aromatic stacking interaction was coupled with stronger intermolecular hydrogen bonding interaction, making peptide molecules tend to adopt β-turn conformation. Similar to KRW6, KRW6-F, and KRW6-FF peptides, KKRW6-F peptide with larger number of aromatic amino acids also showed stronger intermolecular hydrogen bonding interaction and stronger tendency to adopt β-turn conformation than KKRW6 peptide, showing the important influences of aromatic motifs.

4 Conclusion

Peptide self-assembly is a spontaneous process forced by weak molecular interactions. In this work, the five aromatic AMPs had similar peptide sequences, but the microscopic structures and secondary conformations were different. It was found that the peptides with larger number of aromatic amino acids tended to have stronger intermolecular hydrogen bonding and aromatic stacking interactions and were more likely to adopt β-turn conformation; the peptides with smaller number of aromatic amino acids tended to have stronger intramolecular hydrogen bonding interaction and were more likely to adopt β-sheet conformation. However, the effects of aromatic amino acids on the microscopic structure of self-assemblies were more complex and still needed to be revealed in the future.

Funding information: This work was financially supported by the National Natural Science Foundation of China (No. 51703260, 51603236), and Program for Science and Technology of Henan Province (No. 212102210292).
Author contributions: Fengyi Cao: conceptualization, methodology, data curation, writing – original draft, and writing – review and editing; Genxing Zhu: formal analysis and validation; Meng Song: formal analysis and validation; Xiaoli Zhao: methodology and formal analysis; Gangqing Ma and Mengqing Zhang: methodology.
Conflict of interest: Authors declare no conflict of interest.

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Received: 2021-09-30

Revised: 2021-10-29

Accepted: 2021-11-03

Published Online: 2022-03-16

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/epoly-2022-0012

Keywords for this article

antimicrobial peptide; self-assembly; microscopic structure; secondary conformation; molecular interaction

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BY 4.0