Antiparallel Β-sheet Research Articles

Molecular dynamics simulations of amyloid-β(16-22) peptide aggregation at air-water interfaces.

Oligomers of amyloid-β (Aβ) peptides are known to be related to Alzheimer's disease, and their formation is accelerated at hydrophilic-hydrophobic interfaces, such as the cell membrane surface and air-water interface. Here, we report molecular dynamics simulations of aggregation of Aβ(16-22) peptides at air-water interfaces. First, 100 randomly distributed Aβ(16-22) peptides moved to the interface. The high concentration of peptides then accelerated their aggregation and formation of antiparallel β-sheets. Two layers of oligomers were observed near the interface. In the first layer from the interface, the oligomer with less β-bridges exposed the hydrophobic residues to the air. The second layer consisted of oligomers with more β-bridges that protruded into water. They are more soluble in water because the hydrophobic residues are covered by N- and C-terminal hydrophilic residues that are aligned well along the oligomer edge. These results indicate that amyloid protofibril formation mainly occurs in the second layer.

The Amide I Spectrum of Proteins—Optimization of Transition Dipole Coupling Parameters Using Density Functional Theory Calculations

The amide I region of the infrared spectrum is related to the protein backbone conformation and can provide important structural information. However, the interpretation of the experimental results is hampered because the theoretical description of the amide I spectrum is still under development. Quantum mechanical calculations, for example, using density functional theory (DFT), can be used to study the amide I spectrum of small systems, but the high computational cost makes them inapplicable to proteins. Other approaches that solve the eigenvalues of the coupled amide I oscillator system are used instead. An important interaction to be considered is transition dipole coupling (TDC). Its calculation depends on the parameters of the transition dipole moment. This work aims to find the optimal parameters for TDC in three major secondary structures: α-helices, antiparallel β-sheets, and parallel β-sheets. The parameters were suggested through a comparison between DFT and TDC calculations. The comparison showed a good agreement for the spectral shape and for the wavenumbers of the normal modes for all secondary structures. The matching between the two methods improved when hydrogen bonding to the amide oxygen was considered. Optimal parameters for individual secondary structures were also suggested.

The structure of the Legionella response regulator LqsR reveals amino acids critical for phosphorylation and dimerization.

The water-borne bacterium Legionella pneumophila replicates in environmental protozoa and upon inhalation destroys alveolar macrophages, thus causing a potentially fatal pneumonia termed 'Legionnaires' disease'. L. pneumophila employs the Legionella quorum sensing (Lqs) system to control its life cycle, pathogen-host cell interactions, motility and natural competence. Signaling through the Lqs system occurs through the α-hydroxyketone compound Legionella autoinducer-1 (LAI-1) and converges on the prototypic response regulator LqsR, which dimerizes upon phosphorylation of the conserved aspartate, D108 . In this study, we determine the high-resolution structure of monomeric LqsR. The structure reveals a receiver domain adopting a canonical (βα)5 fold, which is connected through an additional sixth helix and an extended α5-helix to a novel output domain. The two domains delineate a mainly positively charged groove, and the output domain adopts a five-stranded antiparallel β-sheet fold similar to nucleotide-binding proteins. Structure-based mutagenesis identified amino acids critical for LqsR phosphorylation and dimerization. Upon phosphorylation, the LqsRD172A and LqsRD302N/E303Q mutant proteins dimerized even more readily than wild-type LqsR, and no evidence for semi-phosphorylated heterodimers was obtained. Taken together, the high-resolution structure of LqsR reveals functionally relevant amino acid residues implicated in signal transduction of the prototypic response regulator.

Roles of four enzyme crosslinks on structural, thermal and gel properties of potato proteins

To form effectively the three-dimensional network structure of potato protein, transglutaminase, laccase, tyrosinase or peroxidase was used to catalyse the covalent crosslinking of protein, respectively, and the structural, crystalline, thermal and gel properties of enzyme-treated proteins were compared. The results indicated that compared to native protein, random coil remarkably reduced by over 50% and β-sheet content, antiparallel β-sheet and β-turn increased by over 30%, 65% and 45%, respectively. The relative crystallinities increased from 7.5 to 8.6–11.8% after enzyme treatments. Enzyme-treated proteins had the higher thermal degradation temperatures (326.91–336.68 °C) and residue quantity (26.05–28.75%), and lower weight loss (68.43–70.13%) than native protein (322.32 °C, 71.72% and 21.80%). Transglutaminase- and peroxidase-treated protein gels displayed the more homogeneous three-dimensional networks with the larger pore sizes, whereas laccase- and tyrosinase-treated protein gels exhibited the less homogeneous networks with the smaller pore sizes. Similarly, the first two protein gels had higher storage modulus and stronger gel strength, whereas the latter two protein gels had lower storage modulus and weaker gel strength. The outcome may offer a significative insight on the theoretical basis to purposefully change structural, thermal and gel properties of potato protein in exploring novel potato staple foods with high qualities.

CDNA Cloning and Characterization of the House Dust Mite Allergen Sui p 2

Suidasia pontifica (Sp) is a House Dust Mite (HDM) species found in tropical urban residential areas which causes sensitization of up to 75% of allergic patients. Cloning of allergens from Sp is a significant initial step in understanding the clinical significance of this HDM species. The study describes the cloning and in silico characterization of the group 2 allergen gene from Sp (Sui p 2) with significant homology to Myeloid Differentiation 2 (MD-2) lipid-binding (ML domain) protein allergens. Sui p 2 gene was amplified by Reverse Transcription – PCR using gene-specific primers designed from known HDM group 2 allergens. The amplicons were characterized using NCBI BLAST, ExPASy, MEGA7 and Chimera. Sui p 2 cDNA gene exhibits percent identity to Tyrophagus putrescentiae (65.84%), Aleuroglyphus ovatus (65.69%) and Blomia tropicalis (62.98%). Sui p 2 gene contains 405 bp open reading frame with untranslated regions on its 5’ and 3’ end. Furthermore, structure-based percent identity of Sui p 2 to the group 2 allergen of D. farinae and D. pteronyssinus is 47.62% and 46.83%, respectively. Predicted protein structure reveals a putative immunoglobulin fold consisting of preserved cysteine residues, hydrophobic core and two antiparallel β-sheets containing several TLR4, LPS and IgE binding sites. The results suggest that Sui p 2 may play an important role in HDM induced allergy and may be involved in the induction of the innate immune system. Characterization of Sui p 2 is important to evaluate properly its use for allergy component resolved diagnosis and allergen-specific immunotherapy.

Influence of oligoribonucleotides on the conformation and stability of interferon

Aim. To study the ability of yeast RNA oligoribonucleotides (ORNs) and their complexes withD-mannitol to influence the conformation and thermal stability of interferon (INF) α-2b. Methods. The ability of oligoribonucleotide drugs to bind to INF α-2b was studied using its fluorescence quenching method. The effect of ORN drugs on protein stability was studied by analyzing the thermal stability of INF. To confirm their influence on the conformation of the INF, we investigated the spectra of circular dichroism. Results. The ORN complexes with D-mannitol, due to their better protein binding, have been shown to have a much higher effect on the conformation and thermal stability of interferon α-2b than ORN. ORNs and their complexes with D-mannitol also increase the thermal stabilization of interferon. The addition of ORN and ORN with D-mannitol to INF leads to a decrease in the content of α-helical components in the protein structure and an increase in β-components and unstructured parts of the protein molecule. Addition of the ORN complex: D-mannitol, unlike the ORN, changes the architecture of the tertiary INF structure. Conclusions. Therefore, the ORN complexes with D-mannitol have a much higher effect on the conformation and thermal stability of interferon α-2b than the parent drug ORN. The more specific binding of oligonucleotides can probably explain this in the presence of mannitol to the protein. ORNs and ORN complexes with D-mannitol also increase the thermal stabilization of interferon by 2 and 1.8 °C, respectively. The addition of ORNs and ORN complexes with D-mannitol leads to a decrease in the content of α- helical components in the protein structure and an increase in antiparallel β-sheets, β-turns, and unstructured elements. In the presence of mannitol in the ORN molecule, the structure of INF changes more intensively. Addition of ORN complexes: D-mannitol to INF, unlike ORN, changes the architecture of the tertiary protein structure from a 2-layer sandwich to an alpha-beta complex.Keywords: oligonucleotides; interferon; mannitol; secondary protein structure.

Enhancing the Usability of Pea Protein Isolate in Food Applications through Modifying Its Structural and Sensory Properties via Deamidation by Glutaminase.

This study aimed to demonstrate the feasibility of improving the properties of pea protein isolate (PPI) related to food applications via deamidation with glutaminase. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Fourier transform infrared (FT-IR) profiling revealed that the current glutaminase treatment did not change the basic protein subunit composition. However, it allowed a certain extent of protein unfolding and conformational reorganization to generate more flexible and extended proteins with reduced average particle size and more hydrophobic groups exposed. The underlying mechanisms might include the reduction of β-sheets and antiparallel β-sheets and the increase of the β-turn structure. Moreover, the treatment time was of importance. A 12 h treatment was generally better than a 24 h treatment, and PPI treated with glutaminase at 50 °C for 12 h to a degree of deamidation of 56.1% exhibited significantly improved solubility, homogeneity, dispersibility, and suspendability with reduced beany flavor, grittiness, and lumpiness (compared to those of the untreated PPI). Thus, the glutaminase treatment offers a promising approach for enhancing the usability and applicability of pea proteins.

Stability of Aβ11-40 Trimers with Parallel and Antiparallel β-Sheet Organizations in a Membrane-Mimicking Environment by Replica Exchange Molecular Dynamics Simulation.

The aggregation of the amyloid (Aβ) peptide of 39-43 amino acids into plaques is observed in the brain of Alzheimer's disease (AD) patients, but the mechanisms underlying the neurotoxicity of Aβ oligomers are still elusive. One suggested initial mechanism is related to the implications of amyloid membrane interactions, but characterization of these assemblies is challenging by experimental means. In this study, we have explored the stability of a trimer of Aβ11-40 in parallel and antiparallel β-sheet structures for the wild-type sequence and its F20W mutant in a dipalmitoylphosphatidylcholine membrane using atomistic replica exchange molecular dynamic simulations. We show that both the U-shape organization and the assembly of β-hairpins are maintained in the membrane and are resistant to the mutation F20W. In contrast the models are destabilized by the F19P mutation. Overall, our results indicate that these two assemblies represent minimal seeds or nuclei for the formation of either amyloid fibrils, a variety of β-barrel pores, or various aggregates for many Aβ sequences in a membrane-mimicking environment.

Biophysical characterization of p53 core domain aggregates.

Aggregation is the cause of numerous protein conformation diseases. A common facet of these maladies is the transition of a protein from its functional native state into higher order forms, such as oligomers and amyloid fibrils. p53 is an essential tumor suppressor that is prone to such conformational transitions, resulting in its compromised ability to avert cancer. This work explores the biophysical properties of early-, mid-, and late-stage p53 core domain (p53C) aggregates. Atomistic and coarse-grained molecular dynamics (MD) simulations suggest that early- and mid-stage p53C aggregates have a polymorphic topology of antiparallel and parallel β-sheets that localize to the core amyloidogenic sequence. Both topologies involve similar extents of interstrand mainchain hydrogen bonding, while sidechain interactions could play a role in regulating strand orientation. The free energy difference between the antiparallel and parallel states was within statistical uncertainty. Negative stain electron microscopy of mature fibrils shows a wide distribution of fiber widths, indicating that polymorphism may extend to the quaternary structure level. Circular dichroism of the fibrils was indicative of β-sheet rich structures in atypical conformations. The Raman spectrum of aggregated p53C was consistent with a mixture of arranged β-sheets and heterogeneous structural elements, which is compatible with the MD findings of an ordered β-sheet nucleus flanked by disordered structure. Structural polymorphism is a common property of amyloids; however, because certain polymorphs of the same protein can be more harmful than others, going forward it will be pertinent to establish correlations between p53C aggregate structure and pathology.

Structural Characterization of the CD44 Stem Region for Standard and Cancer-Associated Isoforms.

CD44 is widely expressed in most vertebrate cells, whereas the expression of CD44v6 is restricted to only a few tissues and has been considered to be associated with tumor progression and metastasis. Thus, CD44v6 has been recognized as a promising prognostic biomarker and therapeutic target for various cancers for more than a decade. However, despite many experimental studies, the structural dynamics and differences between CD44s and CD44v6, particularly in their stem region, still remain elusive. Here, a computational study was conducted to address these problems. We found that the stem of CD44s adopted predominantly two conformations, one featuring antiparallel β-sheets and the other featuring parallel β-sheets, whereas the stem of CD44v6 adopted mainly one conformation with relatively highly suppressed β-sheet contents. Moreover, Phe215 was found to be essential in the β-sheets of both CD44s and CD44v6. We finally found intramolecular Phe215–Trp224 hydrogen-bonding interactions and hydrophobic interactions with Phe215 that cooperatively drove conformational differences upon the addition of the v6 region to CD44. Our study elucidated the structural differences between the stem regions of CD44s and CD44v6 and thus can offer useful structural information for drug design to specifically target CD44v6 in promising clinical applications.

Comparative evaluation of physicochemical, nutritional and molecular interactions of flours from different cereals as affected by germination duration

The cereal grains (wheat, rice, oats and maize) were germinated from 24 to 72 h for different time with the aim to increase their antioxidant activity, RDS (rapidly digestible starch) and low resistant starch (RS) fractions. Upon germination for 24 h, the protein, fat, fiber and ash content of different cereal grains decreased from 13.7 to 12.5%, 1.7 to 1.2%, 1.08 to 1.05% and 1.32 to 1.27% respectively. The germinated flours from different cereals contributed to the advanced molecular interactions between proteins and starch. The FTIR analysis revealed the evident changes in the spectral intensity among the germinated cereal flours. The amide I bands occur due to C=O straightening of the peptide group. The proportion of α-helix and β-sheet were highest in wheat flour while maize flour had the highest section of β-turns and anti-parallel β-sheets. The proportion of secondary proteins decreased with the progression in germination period. The germination significantly decreased the total starch content and causes the depolymerization of starch molecules. The continuous reduction of viscosity was observed with the progress in germination. Overall, this study summarizes that the germination can be used as the effective natural bio-processing technique to develop modified cereal flours with enhanced nutritional properties and promote possible interactions of the flour components aimed towards the emphasis of both starch and protein digestion rates.

Structural insights into the catalytic mechanism of lovastatin hydrolase

Structural insights into the catalytic mechanism of lovastatin hydrolase

Structure-rheology relationship of basil seed gum-whey protein isolate mixture: Effect of thermal treatment and biopolymer ratio

In this paper, the changes in some physicochemical properties of basil seed gum: whey protein isolate (BSG: WPI) blends were investigated and their correlation with the rheological properties was assessed under different biopolymers ratio and temperatures. To simplify the discussion, total 36 generated rheological parameters were clustered in five groups. Subsequently, the effect of biopolymers ratio (1:0, 1:4 & 1:9 BSG: WPI) and thermal treatment (25 °C & 80 °C for 30 min) were discussed on one parameter from each category. Furthermore, the intensity of the amide I and amide II bands and the percentage area of the curve fitting at around 1632, 1649 and 1683 cm−1 were assessed at different conditions. Generally, heating improved the rheological properties of 1:4 BSG: WPI. Regarding the percentage of 1683 cm−1 band area of different samples, WPI in blends showed lower formation of intermolecular antiparallel β-sheets than in pure WPI dispersion. Also, a partial conversion of β-sheet into α-helix/unordered structure happened at low added BSG blend, i.e., 1:9 BSG: WPI dispersion, whereas, at higher BSG content, i.e., 1:4 BSG: WPI dispersion, β-sheet remained as the main structure of WPI. Unheated and heated 1:4 BSG: WPI showed a lower antagonistic behavior based on apparent viscosity (50 s−1) than 1:9 BSG: WPI. In addition, both blends showed lower antagonistic behavior after heating. Results proposed that different temperatures and biopolymer ratios of BSG: WPI can be utilized to create products that exhibit a variety of different rheological and physicochemical characteristics.

Effect of wet and dry milling on the functional properties of whole sorghum grain flour and kafirin.

The effect of wet and dry milling on the functional properties of whole sorghum grain flour (SF) and extracted kafirin were assessed. White sorghum landrace was used to prepare two SFs by wet milling (SF1) or dry milling (SF2) and to extract their respective kafirins SK1 and SK2. Protein contents of SK1 and SK2 were 90.07 and 94.23%. Wet milling of SF allowed increasing the oil binding capacity, the least gelling concentration and the instant foam capacity and decreasing the water binding capacity and foam stability. The emulsifying activity index of SF1 and SF2 were in the same range, while emulsion stability was two time higher in SF2. Functional properties of SK1 and SK2 showed an appropriate water binding capacity of 2.20 ± 0.10 and 1.82 ± 0.22 (g water/g dry mater), respectively. Both SK1 and SK2 showed higher oil binding capacity than SF1 and SF2 with no gel and foam formation. The wet milling improved water and oil binding capacities of SK1 by 17 and 5%. The emulsifying activity indexes were approximately similar for SK1 and SK2 with emulsion stability exceeding 60%. Fourier transform infrared spectroscopy of SK1 and SK2 showed that wet milling induced a decrease of α-helical structure and an increase of intermolecular β-sheet and β-turns and no change in the anti parallel β-sheet. This study showed that wet milling could allow extracting kafirin with preserving the most important functional properties of SF and kafirin and could constitute an interesting method for protein recovery and starch isolation.

Improved Stability and Tunable Functionalization of Parallel β-Sheets via Multicomponent N-Alkylation of the Turn Moiety.

In contrast to the myriad of methods available to produce α‐helices and antiparallel β‐sheets in synthetic peptides, just a few are known for the construction of stable, non‐cyclic parallel β‐sheets. Herein, we report an efficient on‐resin approach for the assembly of parallel β‐sheet peptides in which the N‐alkylated turn moiety enhances the stability and gives access to a variety of functionalizations without modifying the parallel strands. The key synthetic step of this strategy is the multicomponent construction of an N‐alkylated turn using the Ugi reaction on varied isocyano‐resins. This four‐component process assembles the orthogonally protected turn fragment and incorporates handles serving for labeling/conjugation purposes or for reducing peptide aggregation. NMR and circular dichroism analyses confirm the better‐structured and more stable parallel β‐sheets in the N‐alkylated peptides compared to the non‐functionalized variants.

Ultra-thin free-floating carbon nanotube/gold nanoparticle hybrid film prepared with self-assembly protein of α-synuclein

Fabrication of ultra-thin 2D film of carbon nanotubes (CNTs) is achieved by employing a self-assembly protein of α-synuclein (αS). Electron energy loss spectroscopy-transmission electron microscopy and circular dichroism spectroscopy analyses indicate that αS binds to the hydrophobic surface of CNT through its N-terminal region by forming α-helix. 1H-15N heteronuclear single-quantum coherence correlation-nuclear magnetic resonance spectra show that the acidic C-terminus of αS is exposed outward from the CNT surface. Following a slow vacuum filtration of the CNTs complexed with αS through a polycarbonate membrane filter, chloroform is used to unleash the free-floating ultra-thin CNT film from the substrate by causing unique αS-αS interactions of the enhanced anti-parallel β-sheet and α-helix formation. To make a graphically patterned CNT film stable in the free-floating state, gold nanoparticles (AuNPs) encapsulated with αS are employed to generate the αS-mediated CNT/AuNP hybrid film. The CNT-AuNP hybrid pattern is also directly transferred onto a thermo-responsive hydrogel sheet and sandwiched with a passive polymer layer. The resulting triply structure exhibits a shape deformation upon the light exposure. The light-responsive controllable soft material, therefore, has been suggested to be utilized in various areas including not only soft robotics but also human-machine interface by providing stimuli-responsive electroconductive and biocompatible matrix.

Partial Characterization of Two Cathepsin D Family Aspartic Peptidases of Clonorchis sinensis.

Cathepsin D (CatD, EC 3.4.23.5) is a member belonging to the subfamily of aspartic endopeptidases, which are classified into the MEROPS clan AA, family A1. Helminth parasites express a large set of different peptidases that play pivotal roles in parasite biology and pathophysiology. However, CatD is less well known than the other classes of peptidases in terms of biochemical properties and biological functions. In this study, we identified 2 novel CatDs (CsCatD1 and CsCatD2) of Clonorchis sinensis and partially characterized their properties. Both CsCatDs represent typical enzymes sharing amino acid residues and motifs that are tightly conserved in the CatD superfamily of proteins. Both CsCatDs showed similar patterns of expression in different developmental stages of C. sinensis, but CsCatD2 was also expressed in metacercariae. CsCatD2 was mainly expressed in the intestines and eggs of C. sinensis. Sera obtained from rats experimentally infected with C. sinensis reacted with recombinant CsCatD2 beginning 2 weeks after infection and the antibody titers were gradually increased by maturation of the parasite. Structural analysis of CsCatD2 revealed a bilobed enzyme structure consisting of 2 antiparallel β-sheet domains packed against each other forming a homodimeric structure. These results suggested a plausible biological role of CsCatD2 in the nutrition and reproduction of parasite and its potential utility as a serodiagnostic antigen in clonorchiasis.

PDZ/PDZ interaction between PSD-95 and nNOS neuronal proteins: A thermodynamic analysis of the PSD95-PDZ2/nNOS-PDZ interaction.

N-Methyl-D-aspartate (NMDA) receptors are key components in synaptic communication and are highly relevant in central nervous disorders, where they trigger excessive calcium entry into the neuronal cells causing harmful overproduction of nitric oxide by the neuronal nitric oxide synthase (nNOS) protein. Remarkably, NMDA receptor activation is aided by a second protein, postsynaptic density of 95 kDa (PSD95), forming the ternary protein complex NMDA/PSD95/nNOS. To minimize the potential side effects derived from blocking this ternary complex or either of its protein components, a promising approach points to the disruption of the PSD-95/nNOS interaction which is mediated by a PDZ/PDZ domain complex. Since the rational development of molecules targeting such protein-protein interaction relies on energetic and structural information herein, we include a thermodynamic and structural analysis of the PSD95-PDZ2/nNOS-PDZ. Two energetically relevant events are structurally linked to a "two-faced" or two areas of recognition between both domains. First, the assembly of a four-stranded antiparallel β-sheet between the β hairpins of nNOS and of PSD95-PDZ2, mainly enthalpic in nature, contributes 80% to the affinity. Second, binding is entropically reinforced by the hydrophobic interaction between side chains of the same nNOS β-hairpin with the side chains of α2-helix at the binding site of PSD95-PDZ2, contributing the remaining 20% of the total affinity. These results suggest strategies for the future rational design of molecules able to disrupt this complex and constitute the first exhaustive thermodynamic analysis of a PDZ/PDZ interaction.

Regular Exercise Participation Contributes to Better Proteostasis, Inflammatory Profile, and Vasoactive Profile in Patients With Hypertension.

Physical exercise is a well-established strategy to control blood pressure. Nonetheless, its effects on protein homeostasis in individuals with hypertension are not clearly defined. Evaluate proteostasis, quality of life, and inflammation, oxidative stress, and vasoactive biomarkers in adults with hypertension regarding reported exercise habits. Twenty individuals were recruited in a health-care centre, 10 regular exercisers (age: 68.3 ± 4.2 years) and 10 age-matched individuals without regular exercise participation (age: 67.7 ± 5.1 years). Proteostasis and the levels of ubiquitin, heat shock protein 70 (Hsp70), endothelial nitric oxide synthase (eNOS), matrix metalloproteinases 2 (MMP-2), tissue inhibitor of MMP-2 (TIMP-2), connexin 43 (Cx43) and extracellular superoxide dismutase-3 (SOD-3) were assessed in plasma using immunoblotting techniques (western blot or slot blot) and Fourier-transform infrared spectroscopy (FTIR). Quality of life was assessed using the Short Form 36 (SF-36) version 2.0 questionnaire. Significant higher levels of interleukin (IL)-6 (P = 0.014), eNOS (P = 0.011), Cx43 (P = 0.020), TIMP-2 (P = 0.038), and SOD-3 (P = 0.001), with a fold increase of 1.5, 1.2, 2.1, 1.3, and 1.2, respectively, were found in the exercise group. The overall quality of life (60.1 ± 4.3 vs. 53.2 ± 5.9, P = 0.009), as well as mental health domain (59.4 ± 7.9 vs. 50.7 ± 7.2, P = 0.024) were significantly higher in the exercise group. Multivariate analysis by FTIR showed that the age-matched group is characterized by peaks related with antiparallel β-sheet, whereas exercise group is characterized by peaks related to random coils, β-sheet, and α-helix. Individuals with regular exercise participation showed better proteostasis, quality of life, inflammatory profile, antioxidant defenses, and eNOS levels.

Stabilization of Cyclic β-Hairpins by Ugi-Reaction-Derived N-Alkylated Peptides: The Quest for Functionalized β-Turns

A solid-phase approach including on-resin Ugi reactions was developed for the construction of β-hairpins. Various N-alkylated dipeptide fragments proved capable of aligning antiparallel β-sheets in a macrocyclic scaffold, thus serving as β-hairpin templates. Gramicidin S was used as the model β-hairpin to compare the Ugi-derived β-turns with the type-II' β-turn. The results show that the multicomponent incorporation of such N-alkylated residues allows for the simultaneous stabilization and exo-cyclic functionalization of cyclic β-hairpins.