A helix-forming αβγ-chimeric peptide with catalytic activity: a hybrid peptide ligase

We describe the catalytic activity of the first chimeric ligase containing a foldameric sequence of β- and γ-amino acids. The chimeric backbone provides for the spatial arrangement of all functional groups involved in the formation of the catalytic site to allow efficient catalysis to take place. Our finding indicates significant progress in the field of functionally active artificial motifs.     

How does a hydrocarbon staple affect peptide hydrophobicity?

Water is essential for the proper folding of proteins and the assembly of protein–protein/ligand complexes. How water regulates complex formation depends on the chemical and topological details of the interface. The dynamics of water in the interdomain region between an E3 ubiquitin ligase (MDM2) and three different peptides derived from the tumor suppressor protein p53 are studied using molecular dynamics. The peptides show bimodal distributions of interdomain water densities across a range of distances. The addition of a hydrocarbon chain to rigidify the peptides (in a process known as stapling) results in an increase in average hydrophobicity of the peptide–protein interface. Additionally, the hydrophobic staple shields a network of water molecules, kinetically stabilizing a water chain hydrogen‐bonded between the peptide and MDM2. These properties could result in a decrease in the energy barrier associated with dehydrating the peptide–protein interface, thereby regulating the kinetics of peptide binding. © 2015 Wiley Periodicals, Inc.     

Discovery of a potent and highly β1 specific proteasome inhibitor from a focused library of urea-containing peptide vinyl sulfones and peptide epoxyketones

Syringolins, a class of natural products, potently and selectively inhibit the proteasome and show promising antitumour activity. To gain insight in the mode of action of syringolins, the ureido structural element present in syringolins is incorporated in oligopeptide vinyl sulfones and peptide epoxyketones yielding a focused library of potent new proteasome inhibitors. The distance of the ureido linkage with respect to the electrophilic trap strongly influences subunit selectivity within the proteasome. Compounds 13 and 15 are β5 selective and their potency exceeds that of syringolin A. In contrast, 5 may well be the most potent β1 selective compound active in living cells reported to date.     

An amyloid-like fibril-forming supramolecular cross-β-structure of a model peptide: a crystallographic insight

The peptide Boc-Val-Phe-OMe 1 bearing sequence similarity with the central hydrophobic cluster (CHC) of Alzheimer's Aβ(18-19) peptide self-assembles to produce amyloid-like straight unbranched fibrils as examined by atomic force microscopy and Congo red assay. Single crystal X-ray diffraction offers the atomic level structure of the supramolecular parallel β-sheet aggregation and antiparallel separation between layers (cross-β-structure).     

Nucleation of β-hairpin structure in a pyrrole amino acid containing peptide

Synthesis and conformational studies of two short peptides containing pyrrole amino acids (1, Paa), Boc-Paa-Paa-d-Pro-Gly-Xaa-Paa-Paa-OMe (2: Xaa=Ala; 3: Xaa=Val), were carried out in which it was established that replacement of Ala in 2 with a Val residue helps peptide 3 to adopt a well-defined β-hairpin conformation in a nonpolar solvent, like CDCl₃.     

Dynamic relaying properties of a β-turn peptide in long-range electron transfer

The relay stations play a significant role in long-range charge hopping transfer in proteins. Although studies have clarified that many more protein structural motifs can function as relays in charge hopping transfers by acting as intermediate charge carriers, the relaying properties are still poorly understood. In this work, taking a β-turn oligopeptide as an example, we report a dynamic character of a relay with tunable relaying properties using the density functional theory calculations. Our main finding is that a β-turn peptide can serve as an effective electron relay in facilitating long-range electron migration and its relay properties is vibration-tunable. The vibration-induced structural transient distortions remarkably affect the lowest occupied molecular orbital (LUMO) energy, vertical electron affinity and electron-binding mode of the β-turn oligopeptide and the singly occupied molecular orbital (SOMO) energy of the corresponding electron adduct and thus the relaying properties. Different vibration modes lead to different structural distortions and thus have different effects on the relaying properties and ability of the β-turn peptide. For the relaying properties, there approximately is a linear negative correlation of electron affinity with the LUMO energy of the β-turn or the SOMO energy of its electron adduct. Besides, such relaying properties also vary in the vibration evolution process, and the electron-binding modes may be tunable. As an important addition to the known static charge relaying properties occurring in various protein structural motifs, this work reports the dynamic electron-relaying characteristics of a β-turn oligopeptide with variable relaying properties governed by molecular vibrations which can be applied to different proteins in mediating long-range charge transfers. Clearly, this work reveals molecular vibration effects on the electron relaying properties of protein structural motifs and provides new insights into the dynamics of long-range charge transfers in proteins. © 2018 Wiley Periodicals, Inc.     

Bifunctional compounds for controlling metal-mediated aggregation of the aβ42 peptide

Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer's disease (AD). Disruption of these metal-peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu(2+) and Zn(2+) and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal-mediated aggregation of the Aβ(42) peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ(42) oligomers in the presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ(42) peptide-in contrast to the Aβ(40) peptide-the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ(42) oligomers.     

Prepatellamide A, a new cyclic peptide from the ascidian Lissoclinum patella

A new cyclic peptide, prepatellamide A (1), along with three known cyclic peptides (2)-(4), was isolated from the ascidian Lissodinum patella. The structure of prepatellamide A was determined from one- and two-dimensional H and 13C NMR spectra. The known cyclic peptides were identified as patellamides A (2), B (3) and C (4).     

A novel conjugate of a cell-penetrating peptide and a ferrocenyl amino acid: a potential electrochemical sensor for living cells?

The conjugation of a ferrocenyl amino acid to the cell-penetrating peptide hCT(9-32) does not impair its ability to efficiently translocate into cells. Furthermore, the bioconjugate does not induce any cytotoxicity, thus presenting a potential electrochemical sensor suitable for the detection of living cells.     

Concurrent display of both α- and β-turns in a model peptide

This article describes a model peptide that concurrently displays both α- and β-turns, as demonstrated by structural investigations using single crystal X-ray crystallography and solution-state NMR studies. The motif reported herein has the potential for the design of novel conformationally ordered synthetic oligomers with structural architectures distinct from those classically observed.     

Unravelling the interaction between α-cyclodextrin with the thaumatin protein and a peptide mimic

G-protein-coupled receptors (GPCRs) are responsible for signal transduction; through these transmembrane proteins, our senses are evoked: sight, smell and taste. Thaumatin is a natural sweet-tasting protein that is 100,000 times sweeter than sucrose but its use in food products has been hampered due to a liquorice aftertaste. Thaumatin has been shown to bind to a class C GPCR and the active binding site of the thaumatin protein is known. Here, we report on the binding of a well-known food grade host: α-cyclodextrin to thaumatin. We show through a combination of one- and two-dimensional NMR experiments that α-cyclodextrin binds to aromatic residues on thaumatin with K_a = 8.5 ± 2.4 M ^? 1. We also synthesise a heptapeptide KTGDRGF that mimics the active binding site of thaumatin and show that α-cyclodextrin binds to the C-terminal solvent accessible phenylalanine residue of this peptide with K_a = 8.8 ± 3.1 M ^? 1. This indicates that α-cyclodextrin may interact with the active binding site on thaumatin, suggesting that α-cyclodextrin could be used to modify the interaction of thaumatin with GPCRs and hence its sweet-taste profile.     

Metal-amyloid-β peptide interactions: a preliminary investigation of molecular mechanisms for Alzheimer''''s disease

Although humans have spent exactly 100 years combating Alzheimer's disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the population and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2 and Zn2 inducing the aggregation of Aβ, catalysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.     

Interference of a new cyclometallated Pt compound with Cu binding to amyloid-β peptide

Coordination of a cyclometallated Pt(II) complex (1) to an amyloid-β peptide was probed by NMR and ESI-MS. Furthermore, EPR showed that binding of 1 to the Cu(II)-amyloid-β species resulted in a reshuffling of the Cu(II) coordination sphere, which was absent or lower for the sister non cyclometallated Pt(II) complexes.     

Evaluating force field accuracy with long-time simulations of a β-hairpin tryptophan zipper peptide

We have combined graphics processing unit-accelerated all-atom molecular dynamics with parallel tempering to explore the folding properties of small peptides in implicit solvent on the time scale of microseconds. We applied this methodology to the synthetic β-hairpin, trpzip2, and one of its sequence variants, W2W9. Each simulation consisted of over 8 μs of aggregated virtual time. Several measures of folding behavior showed good convergence, allowing comparison with experimental equilibrium properties. Our simulations suggest that the intramolecular interactions of tryptophan side chains are responsible for much of the stability of the native fold. We conclude that the ff99 force field combined with ff96 φ and ψ dihedral energies and an implicit solvent can reproduce plausible folding behavior in both trpzip2 and W2W9.     

On the orientation of a designed transmembrane peptide: toward the right tilt angle?

The orientation of the transmembrane peptide WALP23 under small hydrophobic mismatch has been assessed through long-time-scale molecular dynamics simulations of hundreds of nanoseconds. Each simulation gives systematically large tilt angles (>30 degrees). In addition, the peptide visits various azimuthal rotations that mostly depend on the initial conditions and converge very slowly. In contrast, small tilt angles as well as a well-defined azimuthal rotation were suggested by recent solid-state 2H NMR studies on the same system. To optimally compare our simulations with NMR data, we concatenated the different trajectories in order to increase the sampling. The agreement with 2H NMR quadrupolar splittings is spectacularly better when these latter are back-calculated from the concatenated trajectory than from any individual simulation. From these ensembled-average quadrupolar splittings, we then applied the GALA method as described by Strandberg et al. (Biophys J. 2004, 86, 3709-3721), which basically derives the peptide orientation (tilt and azimuth) from the splittings. We find small tilt angles (6.5 degrees), whereas the real observed tilt in the concatenated trajectory presents a higher value (33.5 degrees). We thus propose that the small tilt angles estimated by the GALA method are the result of averaging effects, provided that the peptide visits many states of different azimuthal rotations. We discuss how to improve the method and suggest some other experiments to confirm this hypothesis. This work also highlights the need to run several and rather long trajectories in order to predict the peptide orientation from computer simulations.     

Synthesis of bifunctional peptide derivatives based on a β-cyclodextrin core with drug delivery potential

A selective, versatile, robust methodology for bifunctionalization of β-cyclodextrin is achieved allowing the attachment of peptides in varying C- and/or N-terminal combinations on resin using Fmoc SPPS. Two linkers are attached to cyclodextrin enabling selective binding to the resin (or a peptide attached to the resin). Continuation of peptide growth and/or cleavage from the resin follows, thus various combinations of peptide-cyclodextrin species are achieved. A model peptide (Gly-Ala) is used in this study to illustrate the potential of this system for attaching one or more bioactive peptides for drug transport and release purposes.