Chiral Fibers Formation Upon Assembly of Tetraphenylalanine Peptide Conjugated to a PNA Dimer

Self-assembly of biomolecules such as peptides, nucleic acids or their analogues affords supramolecular objects, exhibiting structures and physical properties dependent on the amino-acid or nucleobase composition. Conjugation of the peptide diphenylalanine (FF) to peptide nucleic acids triggers formation of self-assembled structures, mainly stabilized by interactions between FF. In this work we report formation of homogeneous chiral fibers upon self-assembly of the hybrid composed of the tetraphenylalanine peptide (4F) conjugated to the PNA dimer adenine-thymine (at). In this case nucleobases seem to play a key role in determining the morphology and chirality of the fibers. When the PNA “at” is replaced by guanine-cytosine dimer “gc”, disordered structures are observed. Spectroscopic characterization of the self-assembled hybrids, along with AFM and SEM studies is reported. Finally, a structural model consistent with the experimental evidence has also been obtained, showing how the building blocks of 4Fat arrange to give helical fibers.     

多肽分子自组装

源于自然界中广泛存在的蛋白质自组装现象,近年来多肽的自组装逐渐成为材料学和生物医学等领域的研究热点.通过合理调控多肽的分子结构以及改变外界的环境,多肽分子可以利用氢键、疏水性作用、π-π堆积作用等非共价键力自发或触发地自组装形成形态与结构特异的组装体.由于多肽自身具有良好的生物相容性和可控的降解性能,利用多肽自组装技术构建的各种功能性材料在药物控制释放、组织工程支架材料以及生物矿化等领域内有着巨大的应用前景.本文总结了近年来多肽自组装研究的进展,介绍了多肽自组装技术常见的几种结构模型,概括了多肽自组装的机理,并进一步阐述多肽自组装形成的组装体形态及其在材料学和生物医学等领域里的应用.     

Research Progress of Regulation of Driving Forces in Short Peptide Supramolecular Self-Assembly北大核心CSCD

Some short peptides can spontaneously self-assemble into various nanostructures via the synergistic driving forces of non-covalent interactions. These non-covalent interactions,including electrostatic interaction,hydrogen bonding,aromatic interactions and other non-covalent interactions,are usually highly coupled together. Through rational sequence design and proper modification of short peptide molecules,the driving forces could be regulated purposively,and the nanostructures and morphologies of the self-assemblies could be controlled accordingly,and thus so as to achieve the fabrication of peptide-based supramolecular biomaterials and develop their functions. In this paper,the effects of hydrogen bonding,π-π stacking, electrostatic interaction,hydrophobic interaction,metal ion coordination and chiral center on the self-assembly behavior of peptide self-assembly have been reviewed. The driving force regulation strategies, including sequence design,pH and concentration adjustment and metal ion coordination,and the resulted nanostructures have also been discussed. We also make the outlooks on the development of peptide-based supramolecular biomaterials with specific functions in biomedicines and biocatalysis. © 2022, Science Press (China). All rights reserved.     

Multiple hydrogen bonding induced self-assembly: transformation from nanofibrils to nanosphere with aromatic oligoamide incorporated polyethylene glycol

Aromatic oligoamides bearing six potential hydrogen-bonding sites were designed and synthesized. Functionalized with two polyethylene glycol (M_w?=?2000), this aromatic oligoamide could self-assemble via hydrogen bonds to form nanofibrils in nonpolar solvents as a result of aggregation. The resulting aggregates were characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM) and dynamic light scattering (DLS). Upon adding another aromatic oligoamide containing complementary hydrogen bond donors and acceptors, transformation from nanofibrils to nanosphere was observed due to formation of hydrogen-bonded duplex. The nanospherical micelle was corroborated by SEM, transmission electron microscopy (TEM) and AFM tests. The results achieved here demonstrate an alternative route to effect supramolecular structures via multiple hydrogen bonding-induced self-assembly process.     

Molecular simulation study of peptide amphiphile self-assembly

We study the self-assembly of peptide amphiphile (PA) molecules, which is governed by hydrophobic interactions between alkyl tails and a network of hydrogen bonds between peptide blocks. We demonstrate that the interplay between these two interactions results in the formation of assemblies of different morphology, in particular, single beta-sheets connected laterally by hydrogen bonds, stacks of parallel beta-sheets, spherical micelles, micelles with beta-sheets in the corona, and long cylindrical fibers. We characterize the size distribution of the aggregates as a function of the molecular interactions. Our results suggest that the formation of nanofibers of peptide amphiphiles obeys an open association model, which resembles living polymerization.     

Noncovalent polymers based on aromatic derivatives of β-cyclodextrin

6-Monotosyl-and 6-mononaphthyl derivatives of β-cyclodextrin have been synthesized, and their self-association abilities have been compared. The quasi-elastic light-scattering study revealed the occurrence of self-organization of mono-6-naphtyl-β-cyclodextrin in dilute aqueous solutions that is responsible for the formation of nanosized aggregates. It is suggested that the driving forces of self-organization are the combination of hydrophobic interactions between the aromatic group of one cyclodextrin molecule and the cavity of the neighboring macrocycle that lead to the formation of noncovalent polymers and hydrogen bonds between these polymers. The absence of intermolecular interactions in the case of mono-6-tosyl-β-cyclodextrin is apparently related to the discrepancy between sizes of the tosyl moiety and of the β-cyclodextrin cavity. The influence of concentration, temperature, pH of solution, and competing low-molecular-mass agents on the self-assembly and stability of supramolecular polymers has been studied.     

Programmed construction of discrete self-assembled cyclic aggregates

Examples for programmed self-assembly of alpha,beta-unsaturated ketoximes carrying a terminal pyridine subunit are described. The solid-state structures of a series of pyridinyl alpha,beta-unsaturated ketoximes 1 were investigated by X-ray structural analysis; this demonstrated that molecules 3-5 predictably form discrete cyclic aggregates stabilized by a network of hydrogen bonds and aromatic interactions.     

Structural Properties of Phenylalanine-Based Dimers Revealed Using IR Action Spectroscopy

Peptide segments with phenylalanine residues are commonly found in proteins that are related to neurodegenerative diseases. However, the self-assembly of phenylalanine-based peptides can be also functional. Peptides containing phenylalanine residues with different side caps, composition, and chemical alteration can form different types of nanostructures that find many applications in technology and medicine. Various studies have been performed in order to explain the remarkable stability of the resulting nanostructures. Here, we study the early stages of self-assembly of two phenylalanine derived peptides in the gas phase using IR action spectroscopy. Our focus lies on the identification of the key intra- and intermolecular interactions that govern the formation of the dimers. The far-IR region allowed us to distinguish between structural families and to assign the 2-(2-amino-2-phenylacetamido)-2-phenylacetic acid (PhgPhg) dimer to a very symmetric structure with two intermolecular hydrogen bonds and its aromatic rings folded away from the backbone. By comparison with the phenylalanine-based peptide cyclic L-phenylalanyl-L-phenylalanine (cyclo-FF), we found that the linear FF dimer likely adopts a less ordered structure. However, when one more phenylalanine residue is added (FFF), a more structurally organized dimer is formed with several intermolecular hydrogen bonds.     

Tuning secondary structure and self-assembly of amphiphilic peptides

Self-assembly is one of nature's mechanisms by which higher order structures are obtained. Two of the main driving forces for self-assembly, hydrophobic interactions and hydrogen bonding, are both present within amphiphilic peptides. Here, it is demonstrated how the intricately interconnected folding and assembly behavior of an N-terminally acylated peptide, with the sequence GANPNAAG, has been tuned by varying its hydrophobic tail and thermal history. The change in interplay between hydrophobic forces and peptide folding allowed the occurrence of different types of aggregation, from soluble peptides with a random coil conformation to aggregated peptides arranged in a beta-sheet assembly, which form helically twisted bilayer ribbons.     

Formation mechanism of supramolecular hydrogels in the presence of L-phenylalanine derivative as a hydrogelator

A novel chiral hydrogelator, L-phenylalanine derivative can self-assemble in aqueous media at different pH values to form supramolecular hydrogels. The images of the FE-SEM indicate that different aggregates of TC(18)PheBu in morphology were formed, which further lead to the formation of spherical crystallites as observed by polarized optical microscope (POM). The FT-IR spectra of the supramolecular hydrogels reveal that intermolecular hydrogen-bonding and hydrophobic interactions are the driving forces for the self-assembly of TC(18)PheBu. Fluorescence spectra of TC(18)PheBu in aqueous solutions in the presence of pyrene as a probe further confirm the importance of hydrophobic interactions for the self-assembly. The circular dichroism (CD) spectra of TC(18)PheBu in supramolecular hydrogels in the presence of KF indicate that the hydrogen-bonding interaction can be disrupted by fluoride ions, which further confirm the importance of hydrogen bonding for the self-assembly of TC(18)PheBu.     

Peptide–Protein Interactions: From Drug Design to Supramolecular Biomaterials

The self-recognition and self-assembly of biomolecules are spontaneous processes that occur in Nature and allow the formation of ordered structures, at the nanoscale or even at the macroscale, under thermodynamic and kinetic equilibrium as a consequence of specific and local interactions. In particular, peptides and peptidomimetics play an elected role, as they may allow a rational approach to elucidate biological mechanisms to develop new drugs, biomaterials, catalysts, or semiconductors. The forces that rule self-recognition and self-assembly processes are weak interactions, such as hydrogen bonding, electrostatic attractions, and van der Waals forces, and they underlie the formation of the secondary structure (e.g., α-helix, β-sheet, polyproline II helix), which plays a key role in all biological processes. Here, we present recent and significant examples whereby design was successfully applied to attain the desired structural motifs toward function. These studies are important to understand the main interactions ruling the biological processes and the onset of many pathologies. The types of secondary structure adopted by peptides during self-assembly have a fundamental importance not only on the type of nano- or macro-structure formed but also on the properties of biomaterials, such as the types of interaction, encapsulation, non-covalent interaction, or covalent interaction, which are ultimately useful for applications in drug delivery.     

Tunable self-assembled peptide amphiphile nanostructures

Peptide amphiphiles are capable of self-assembly into a diverse array of nanostructures including ribbons, tubes, and vesicles. However, the ability to select the morphology of the resulting structure is not well developed. We examined the influence of systematic changes in the number and type of hydrophobic and hydrophilic amino acids on the self-assembly of amphiphilic peptides. Variations in the morphology of self-assembled peptides of the form X(6)K(n) (X = alanine, valine, or leucine; K = lysine; n = 1-5) are investigated using a combination of transmission electron microscopy and dynamic light scattering measurements. The secondary structures of the peptides are determined using circular dichroism. Self-assembly is controlled through a combination of interactions between the hydrophobic segments of the peptide molecules and repulsive forces between the charged segments. Increasing the hydrophobicity of the peptide by changing X to a more lipophilic amino acid or decreasing the number of hydrophilic amino acids transforms the self-assembled nanostructures from vesicles to tubes and ribbons. Changes in the hydrophobicity of the peptides are reflected in changes in the critical micelle concentration observed using pyrene probe fluorescence analysis. Self-assembled materials formed from cationic peptide amphiphiles of this type display promise as carriers for insoluble molecules or negatively charged nucleic acids in drug or gene delivery applications.     

Parsing of the free energy of aromatic–aromatic stacking interactions in solution

We report an analysis of the energetics of aromatic–aromatic stacking interactions for 39 non-covalent reactions of self- and hetero-association of 12 aromatic molecules with different structures and charge states. A protocol for computation of the contributions to the total energy from various energetic terms has been developed and the results are consistent with experiment in 92% of all the systems studied. It is found that the contributions from hydrogen bonds and entropic factors are always unfavorable, whereas contributions from van-der-Waals, electrostatic and/or hydrophobic effects may lead to stabilizing or destabilizing factors depending on the system studied. The analysis carried out in this work provides an answer to the questions “What forces stabilize/destabilize the stacking of aromatic molecules in aqueous-salt solution and what are their relative importance?”     

Self-assembly in aqueous bile salt solutions

The salts of bile acids (“bile salts”) self-assemble in aqueous solution, similar to classical amphiphiles. The micellization is not only driven by the hydrophobic effect, but also hydrogen binding. Moreover, instead of a small, hydrophilic head and a flexible, hydrophobic tail, bile salts are rigid, almost flat molecules with weakly separated hydrophobic and hydrophilic faces. This results in a complex self-assembly behaviour with very distinct aggregate properties. Some characteristics resemble the behaviour of classical amphiphiles, while others are very different and reminiscent of other classes of molecules, for example low-molecular weight gelators or chromonic materials. We review the peculiar properties of bile salt aggregates, concentrating on general trends rather than specific values and comparing them to classical amphiphiles.     

Dramatic specific-ion effect in supramolecular hydrogels

We report on a pronounced specific-ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular weight peptide-based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel-phase materials were formed due to molecular self-assembly, driven by a combination of hydrogen bonding and π-stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc-YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G'?values between 0.8?kPa and 2.4?kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self-assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H-bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self-assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc-VL and Fmoc-LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc-AA. To get more insights into the molecular mechanism, the effect of anions on sol-gel equilibrium was investigated, which indicates the observed changes result from the specific-ion effects on gels structure, rather than on the sol-gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self-assembly.     

Elementary building blocks of self-assembled peptide nanotubes

In the world of biology, "self-assembly" is the ability of biological entities to interact with one another to form supramolecular structures. One basic group of self-assembled structures is peptide nanotubes (PNTs). However, the self-assembly mechanism, with its special characteristics, is not yet fully understood. An exceptional quantum-confined approach is shown here for the self-assembly mechanism in bio-inspired materials. We found the elementary building block of the studied PNT, which is self-assembled from short peptides composed of two phenylalanine residues, to be 0D-quantum-confined (can be related to confinement in 3D), also called a quantum dot (QD). This elementary building block can further self-assemble to a PNT formation. It has been observed that the assembly process of dots to tubes and the disassembly process of tubes to dots are reversible. We further show that a similar dipeptide can also self-assemble to a QD-like structure, with different dimensions. The presented peptide QD structures are nanometer-sized structures, with pronounced exciton effects, which may promote the use of an entirely new kind of organic QDs.     

Molecular conformation and packing of peptide beta hairpins in the solid state: structures of two synthetic octapeptides containing 1-aminocycloalkane-1-carboxylic acid residues at the i+2 position of the beta turn

Peptide beta-hairpin formation is facilitated by centrally positioned D-Pro-Xxx segments. The synthetic peptides Boc-Leu-Phe-Val-D-Pro-Ac(6)c-Leu-Phe-Val-OMe (1) and Boc-Leu-Phe-Val-D-Pro-Ac(8)c-Leu-Phe-Val-OMe (2) were synthesized in order to explore the role of bulky 1-aminocycloalkane-1-carboxylic acid residues (Ac(n)c, where n is the number of carbon atoms in the ring), at the i+2 position of the nucleating beta turn in peptide beta hairpins. Peptides 1 and 2 crystallize in the monoclinic space group P2(1) with two molecules in the asymmetric unit. The crystal structures of 1 and 2 provide conformational parameters for four peptide hairpin molecules. In all cases, the central segments adopts a type II' beta-turn conformation, and three of the four possible cross-strand hydrogen bonds are observed. Fraying of the hairpins at the termini is accompanied by the observation of NHpi interaction between the Leu(1)NH group and Phe(7) aromatic group. Cross strand stabilizing interactions between the facing residues Phe(2) and Phe(7) are suggested by the observed orientation of aromatic rings. Anomalous far-UV CD spectra observed in solution suggest that close proximity of the Phe rings is maintained even in isolated molecules. In both peptides 1 and 2, the asymmetric unit consists of approximately orthogonal hairpins, precluding the formation of a planar beta-sheet arrangement in the solid state. Solvent molecules, one dioxane and one water in 1, three water molecules in 2, mediate peptide association. A comparison of molecular conformation and packing motifs in available beta-hairpin structures permits delineation of common features. The crystal structures of beta-hairpin peptides provide a means of visualizing different modes of beta-sheet packing, which may be relevant in developing models for aggregates of polypeptides implicated in disease situations.     

CH/pi interactions in DNA and proteins. A theoretical study

A systematic study of the CH/pi interactions of methane with the purine and pyrimidine bases of nucleic acids and with the lateral chains of the four natural aromatic amino acids has been carried out for the first time. The MPWB1K/6-31+G(d,p) method has shown to be adequate for the study of these weak interactions in which dispersion forces play a main role. It has been shown that two different kinds of clusters exist, depending on whether one or two CH bonds point to the aromatic system. The latter one, which we have called bifurcated, is usually more stable. With regard to aromatic amino acids, our calculations agree with experimental data in the fact that tryptophan leads to the strongest interaction, while hystidine leads to the weakest one. In the case of nucleic acid bases, the differences in binding energies are not large. This is specially true for thymine and uracil, showing that these two bases have a similar acceptor character in CH/pi interactions.     

Structural control of self-assembled nanofibers by artificial beta-sheet peptides composed of D- or L-isomer

A novel method for the control of peptide self-assembly has been developed by using synthetic triblock-type beta-sheet peptides composed of l- or d-amino acid, 1L and 1D, as building blocks. The peptides 1L and 1D self-assemble into beta-sheet nanofibers with left- and right-handed twists, respectively, under appropriate condition. On the other hand, the 1L/1D binary mixture was found to form only globular aggregates at the same condition. Thus, amyloid-like nanofiber formation and its nanostructure could be successfully regulated by the stereospecificity of the constituent peptide species.     

Hydrogen-bonded benzylidenebenzohydrazide macrocycles and oligomers: testing the robust capacity of an amide chain in promoting the formation of vesicles

This Letter describes 2-(2-(dioctylamino)-2-oxoethyl-amino)-2-oxoethoxyl (DOAOE)-tuned self-assembly of vesicles from rigid macrocycles and foldamer-like oligomers. The molecules are prepared through the formation of reversible hydrazone bonds from aldehyde and benzo-hydrazide precursors, which are further facilitated by intramolecular N?H-O hydrogen bonding. SEM, AFM, and fluorescent encapsulation studies reveal that the molecules all self-assemble into vesicular structures in methanol, while similar molecules bearing the triethylene glycol or n-decyl chains do not. The results illustrate that DOAOE is robust in promoting the formation of vesicles for aromatic systems in polar solvents.