Dipeptide Chains Research Articles

Assembly of a Diphenylalanine Peptide Nanotube by Molecular Dynamics Methods

The paper develops an approach to modeling the processes of self-assembly of complex molecular nanostructures by molecular dynamics methods using a molecular dynamics manipulator. Previously, this approach was considered using the example of assembling a phenylalanine helical nanotube from a linear set of chains of phenylalanine (F) molecules of different chirality: left-handed L-F and right-handed D-F chirality L-FF and D-FF. The process of self-assembly of dipeptide chains into helical structures of nanotubes is an imitation of applying certain forces to the existing initial linear structure in order to obtain the final structure of the same chemical composition, but with a different helical geometry. The PUMA-CUDA molecular dynamics simulation software package was used as the main software. Using this tool, one can investigate the formation of helical structures from a linear sequence of any amino acids. A comparative analysis of the structures of nanotubes obtained by assembling by molecular dynamics methods and by their experimental self-assembly was performed using the method of visual differential analysis. It has been established that the obtained data correspond to the law of the sign change of chirality of molecular helical structures with the complication of their hierarchical level of organization.

Influence of the dipeptide linker configuration on the activity of PSMA ligands

Selective ligands of an urea-based prostate specific membrane antigen with a phenylalanine/tyrosine-based dipeptide linker and with a mingled chiral centers configuration and/or substituted aromatic fragments were prepared in seven steps by liquid- and in six steps by solid-phase synthesis. In vitro test for inhibiting the cleavage of N-acetylaspartylglutamate revealed the optimum linker containing l -phenylalanine in the structure on the N-terminus of a dipeptide chain.

6-Oxyindan-1-ones with dipeptide chains

Through N-acylation of a- or b-amino acid units by 2-(3-oxo-2,3-dihydro-1H-inden-5-yloxy)acetic acid using the method of N-hydroxysuccinimide esters new dipeptide indan-1-one derivatives were obtained. In general, the direct interaction of the acetic carboxyl group of the substrate with the amino group of the a- or b-dipeptide is a more productive strategy than the sequential peptidic condensation of the two amino acids.

Frontispiece: Control of Helical Chirality of Ferrocene–Dipeptide Conjugates by the Secondary Structure of Dipeptide Chains

Frontispiece: Control of Helical Chirality of Ferrocene–Dipeptide Conjugates by the Secondary Structure of Dipeptide Chains

Control of Helical Chirality of Ferrocene-Dipeptide Conjugates by the Secondary Structure of Dipeptide Chains.

Controlling helical chirality and creating protein secondary structures in cyclic/acyclic ferrocene-dipeptide bioorganometallic conjugates were achieved by adjusting the conformational flexibility of the dipeptide chains. In systems reported to date, the helical chirality of a conjugate was determined by the absolute configuration of the adjacent amino acid reside. In contrast, it was possible to induce both M- and P-helical chirality, even when the configuration of the adjacent amino acid was the same. It is particularly interesting to note that M-helical chirality was produced in a cyclic ferrocene-dipeptide conjugate composed of the l-Ala-d-Pro-cystamine-d-Pro-l-Ala dipeptide sequence (1), in which a type II β-turn-like secondary structure was established.

Structural Characterization of Chirality‐Organized Ferrocene–Dipeptide Conjugates that Contain Pyridine N‐Oxide Moieties

AbstractTwo ferrocene–dipeptide conjugates, Fc(l‐Ala−l‐Pro−PyO)2 (2) and Fc(l‐Ala−l‐Pro−PyO)1 (3), were synthesized by the introduction of an l‐Ala−l‐Pro dipeptide that contained a C‐terminal pyridine N‐oxide moiety into the ferrocene organometallic scaffold. Single‐crystal X‐ray structure determination of ferrocene–dipeptide conjugate 2, which was composed of two dipeptide chains, confirmed the formation of intramolecular antiparallel β‐sheet‐like hydrogen bonds between the CO (Ala) and NH (Ala of another chain) groups to induce a chirality‐organized structure in which the ferrocenoyl moiety adopted a P‐helical chirality. In the crystal packing of compound 2, the peptide chains adopted a right‐handed molecular arrangement through hydrogen‐bonding interactions. On the contrary, ferrocene–dipeptide conjugate 3, which was composed of only one dipeptide chain, self‐assembled into a tetramer structure through the formation of intermolecular hydrogen bonds and π–π interactions between pyridine N‐oxide moieties.

738. Engineered MicroRNA Silences C9ORF72 Variants in BAC Transgenic Mouse

Amyotrophic Lateral Sclerosis (ALS) is a fatal adult-onset neurodegenerative disease that affects upper and lower motor neurons causing progressive muscle weakening. Respiratory failure is ultimately the cause of death approximately 2-5 years after symptom onset. The recent discovery of an expanded hexanucleotide repeat located in chromosome 9 open reading frame 72(C9ORF72) now accounts for the majority of familial ALS cases as well as frontotemporal dementia (FTD) cases. Analysis of patient brain samples have shown that in the presence of the expansion, C9ORF72 mRNA is reduced and RNA sequences complimentary to the expansion aggregate into nuclear foci. Interestingly this RNA can translate by non-ATG repeat associated (RAN) translation into long dipeptide chains. These findings have led to the three following hypothesis on the pathogenies of C9ORF72: 1) An RNA gain-of-function, in which the expanded RNA foci sequester RNA binding and/or splicing proteins. 2) RAN translation from the repeat expansion generates inclusions of toxic poly-dipeptide proteins. 3) Haploinsufficiency, where decreased levels of mRNA lead to insufficient gene product. Our group has generated mice containing a bacterial artificial chromosome (BAC) composed of exons 1-6 of the human C9ORF72 gene and a 500 repeat hexanucleotide expansion. This mouse model recapitulates the major histopathological features seen in human ALS/FTD patients such as: lower levels of C9ORF72 mRNA, RNA nuclear foci, and the RAN translation products. We have used this mouse as a platform in which to test RNAi therapeutic strategies. To this end we have designed artificial microRNAs that target the human C9ORF72 gene with the purpose of decreasing the mRNA levels to determine if we can reduce the toxic RNA foci and/or RNA dipeptide proteins. We packaged one of the microRNAs into a recombinant adeno-associated virus (rAAV) serotype 9 to use with primary neuron cultures and in vivo experiments. Silencing was initially validated in primary cortical neurons from the C9ORF72 mouse model. Our results suggest that AAV9-mediated microRNA not only reduced the mRNA levels of C9ORF72 but also decreased the presence of the most abundant poly dipeptide (GP). Currently, experiments are underway to silence C9orf72 in vivo via intra cranial ventricular (ICV) injection of this microRNA in C9ORF72 transgenic pups and the results will be presented at the meeting.

Secondary Structures in Phe-Containing Isolated Dipeptide Chains: Laser Spectroscopy vs Quantum Chemistry.

The intrinsic conformational landscape of two phenylalanine-containing protein chain models (-Gly-Phe- and -Ala-Phe- sequences) has been investigated theoretically and experimentally in the gas phase. The near UV spectroscopy (first ππ* transition of the Phe ring) is obtained experimentally under jet conditions where the conformational features can be resolved. Single-conformation IR spectroscopy in the NH stretch region is then obtained by IR/UV double resonance in the ground state, leading to resolved vibrational spectra that are assigned in terms of conformation and H-bonding content from comparison with quantum chemistry calculations. For the main conformer, whose UV spectrum exhibits a significant Franck-Condon activity in low frequency modes involving peptide backbone motions relative to the Phe chromophore, excited state IR spectroscopy has also been recorded in a UV/IR/UV experiment. The NH stretch spectral changes observed in such a ππ* labeling experiment enable us to determine those NH bonds that are coupled to the phenyl ring; they are compared to CC2 excited state calculations to quantify the geometry change upon ππ* excitation. The complete and consistent series of data obtained enable us to propose an unambiguous assignment for the gallery of conformers observed and to demonstrate that, in these two sequences, three conceptually important local structural motifs of proteins (β-strands, 27 ribbons, and β-turns) are represented. The satisfactory agreement between the experimental conformational distribution and the predicted landscape anticipated from the DFT-D approach demonstrates the capabilities of a theoretical method that accounts for dispersive interactions. It also shows that the flaws, inherent to a resonant two-photon ionization detection scheme, often evoked for aromatic chromophores, do not seem to be significant in the case of Phe.

Ferrocene-dipeptide conjugates derived from aminoferrocene and 1-acetyl-1′-aminoferrocene: synthesis and conformational studies

In this study we present the synthesis and conformational analysis of mono- and disubstituted ferrocene bioconjugates bearing dipeptide chains (Boc-AA-AA-Fn-X, AA=Gly, l-Ala, l-Val). The conformational preferences of novel aminoferrocene derived conjugates with X=H, as well as their 1-acetyl analogues (X=COMe), were investigated by spectroscopic techniques (IR, NMR and CD) and corroborated by DFT calculations. Chirally organized structures, stabilized through intrachain hydrogen bonds, prevail in solution when X=H. The resulting 10-membered hydrogen-bond ring is destabilized by heteroannular introduction of an acetyl group when X=COMe.

Probing the γ‐Turn in a Short Proline Dipeptide Chain

The small peptide derived from proline, N-acetyl-prolinamide (Ac-Pro-NH2), has been investigated using a combination of Fourier transform microwave spectroscopy with laser ablation. Spectral signatures belonging to only one conformer have been detected in the supersonic expansion. Rotational constants and nuclear quadrupole coupling constants of the two (14)N nuclei have been used in the characterization of a γ-turn structure in the gas phase, which is stabilized by a CO···HN intramolecular hydrogen bond closing a seven-membered ring. A methyl group internal rotation barrier of 354 cm(-1) has been determined from the analysis of the A-E splittings.

Cell–material interactions on biphasic polyurethane matrix

Cell-matrix interaction is a key regulator for controlling stem cell fate in regenerative tissue engineering. These interactions are induced and controlled by the nanoscale features of extracellular matrix and are mimicked on synthetic matrices to control cell structure and functions. Recent studies have shown that nanostructured matrices can modulate stem cell behavior and exert specific role in tissue regeneration. In this study, we have demonstrated that nanostructured phase morphology of synthetic matrix can control adhesion, proliferation, organization and migration of human mesenchymal stem cells (MSCs). Nanostructured biodegradable polyurethanes (PU) with segmental composition exhibit biphasic morphology at nanoscale dimensions and can control cellular features of MSCs. Biodegradable PU with polyester soft segment and hard segment composed of aliphatic diisocyanates and dipeptide chain extender were designed to examine the effect polyurethane phase morphology. By altering the polyurethane composition, morphological architecture of PU was modulated and its effect was examined on MSC. Results show that MSCs can sense the nanoscale morphology of biphasic polyurethane matrix to exhibit distinct cellular features and, thus, signifies the relevance of matrix phase morphology. The role of nanostructured phases of a synthetic matrix in controlling cell-matrix interaction provides important insights for regulation of cell behavior on synthetic matrix and, therefore, is an important tool for engineering tissue regeneration.

Exploring the Polyamine Regulatory Site of the NMDA Receptor: a Parallel Synthesis Approach

The elongated structures of polyamine inverse agonists such as 1,12-diaminododecane (N12N) and 5-(4-aminobutyl)-2-thiopheneoctanamine (N4T8N) lend themselves to a combinatorial chemistry approach to explore a potential polyamine pharmacophore at the NMDA receptor. Herein we describe more than 100 new analogues of N4T8N obtained by breaking up the long octanamine arm into a dipeptide chain of equivalent length. Solid-phase parallel synthesis based on cross-linked polystyrene and a Wang anchor allowed the low-scale preparation of four small libraries based on the combination of two amino acid residues (out of Gly, Leu, Phe, Lys, phenylglycine, Tyr, Trp, His, and Arg). The obtained compounds were tested as modulators of [(3) H]MK-801 binding to rat brain membranes and of NMDA-induced currents in cultured rat hippocampal neurons. Compounds with two aromatic residues acted as binding inhibitors (inverse agonists). Compounds with two Lys residues acted as binding stimulators (agonists) and had stimulatory and inhibitory effects on NMDA-induced currents, depending on the holding potential. High sensitivity of binding inhibition to spermine was conferred by a Tyr residue, whereas a His residue favored high potency at acidic pH.

Molecular Structures of Dipeptide–Palladium(II) Conjugated Complexes

AbstractThe chiral tridentate 2,6‐pyridinedicarboxamide ligand L1H2 bearing two dipeptide chains (‐L‐Ala‐L‐Pro‐NHBu) was designed. Complexation of L1H2 with Pd(OAc)2 was demonstrated to afford the dipeptide–palladium(II) conjugated complex [(L1)Pd(MeCN)] (1) with an ancillary acetonitrile ligand. In the crystal packing of 1, a right‐handed helical‐like molecular arrangement was observed, wherein each assembly is connected through continuous intermolecular hydrogen bonds together with water molecules. The dipeptide–palladium(II) conjugated complex 1 was studied as a metalloreceptor through metal coordination to accommodate a guest ligand, 4‐aminopyridine, resulting in the formation of the dipeptide–palladium(II) conjugated complex [(L1)Pd(4APy)] (2). Each preorganized helical molecule of 2 is packed in a right‐handed helical‐like molecular arrangement in the crystal packing. The dipeptide–palladium(II) conjugated complex 2 was found to exhibit emission with a maximum at 652 nm in the solid state.

Dipeptide-induced chirality organization

This review describes an outline of dipeptide-induced chirality organization by using molecular scaffolds. A variety of ferrocene-dipeptide conjugates as bioorganometallics are designed to induce chirality-organized structures of peptides. The ferrocene serves as a reliable organometallic scaffold with a central reverse-turn unit for the construction of protein secondary structures via intramolecular hydrogen bondings, wherein the attached dipeptide strands are constrained within the appropriate dimensions. Another interesting feature of ferrocene-dipeptide conjugates is their strong tendency to self-assemble through contribution of available hydrogen bonding sites for helical architectures in solid states. Symmetrical introduction of two dipeptide chains into a urea molecular scaffold is performed to induce the formation of the chiral hydrogen-bonded duplex, wherein each hydrogen-bonded duplex is connected by continuous intermolecular hydrogen bonds to form a double helix-like arrangement.

Synthesis and conformational studies of peptido-squaramide foldable modules: a new class of turn-mimetic compounds

The β-turn unit is one of the most important secondary structure elements in proteins. The access to new conformationally controlled foldable modules can afford compounds with interesting bioactivities. Here, we describe a new family of peptido-squaramide foldable modules based on the considerable potential of the squaramide unit as a hydrogen bond donor and acceptor as well as the low rotational barrier of the C-N bond. The conformational analysis by NMR of these modules in chloroform and acetonitrile solution shows that a disecondary squaramide with the 4-aminobutyric acid in one of its substituents can mimic the β-turn structure driven by the formation of an intramolecular hydrogen bonded ten-membered ring. This structure, although flexible, has been successfully combined with dipeptide chains to induce the formation of a hairpin-like structure driven by the formation of several cross-strand intramolecular hydrogen bonds.

N-Linked Peptidoresorc[4]arene-Based Receptors as Noncompetitive Inhibitors for α-Chymotrypsin

This paper deals with the design, synthesis, and evaluation of a new series of receptors for protein surface recognition. The design of these agents is based around the attachment of four constrained dipeptide chains onto a central resorc[4]arene scaffold. By varying the sequence, nature, and stereochemistry of the chains we prepared anionically functionalized N-linked peptidoresorc[4]arenes 12, 13, and 17 by Pd/C-catalyzed hydrogenation of the corresponding benzyl esters 10, 11, and 16. From this family of receptors we have identified noncompetitive inhibitors of α-chymotrypsin (ChT), which function by binding to the surface of the enzyme in the neighborhood of the active site cleft (K(i) values ranging from 12.4 ± 5.1 μM for free carboxylic acid (+)-12b to 0.76 ± 0.14 μM for benzyl ester (-)-16a). For anionically functionalized receptors 12, 13, and 17 the ChT inhibition is based essentially on electrostatic interaction, and the bound enzyme can be released from the resorcarene surface by increasing the ionic strength, with its activity almost completely restored. For receptors with terminal benzyl ester groups (10 and 16) a hydrophobic network can be suggested.

Exploring Carbohydrate−Peptide Interactions in the Gas Phase: Structure and Selectivity in Complexes of Pyranosides with N-Acetylphenylalanine Methylamide

The physical basis of carbohydrate-peptide interactions has been explored by probing the structures of a series of complexes generated in a solvent-free environment under molecular beam conditions. A combination of double-resonance IR-UV spectroscopy and quantum-chemical calculations has established the structures of complexes of the model, N-acetyl-L-phenylalanine methylamide, bound to the α and β anomers of methyl D-gluco- and D-galactopyranoside as guests. In all cases, the carbohydrates are bound through hydrogen bonding to the dipeptide chain, although with some differing patterns. The amino acid host "engages" with the most suitable pair of neighboring conjugate sites on each carbohydrate; the specific choice depends on the conformation of the peptide backbone and the configuration and conformation of the carbohydrate ligand. None of the structures is supported by "stacking" interactions with the aromatic ring, despite their common occurrence in bound carbohydrate-protein structures.

ChemInform Abstract: Chirality Organization of Peptide Conjugated Molecules in Bioorganometallic Chemistry

AbstractReview: 40 refs.

Design of Ferrocene-Dipeptide Bioorganometallic Conjugates To Induce Chirality-Organized Structures

The highly ordered molecular assemblies in proteins can have a variety of functions, as observed in enzymes, receptors, and the like. Synthetic scientists are constructing bioinspired systems by harnessing the self-assembling properties of short peptides. Secondary structures such as alpha-helices, beta-sheets, and beta-turns are important in protein folding, which is mostly directed and stabilized by hydrogen bonding and the hydrophobic interactions of side chains. The design of secondary structure mimics that are composed of short peptides has attracted much attention, both for gaining fundamental insight into the factors affecting protein folding and for developing pharmacologically useful compounds, artificial receptors, asymmetric catalysts, and new materials. Ferrocenes are an organometallic scaffold with a central reverse-turn unit based on the inter-ring spacing of about 3.3 A, which is a suitable distance for hydrogen bonding between attached peptide strands. The conjugation of organometallic compounds with biomolecules such as amino acids, peptides, and DNA should provide novel systems that reflect properties of both the ferrocene and the biologically derived moieties. In this Account, we focus on recent advances in the design of ferrocene-peptide bioconjugates, which help illustrate the peptidomimetic basis for protein folding and the means of constructing highly ordered molecular assemblies. Ferrocene-peptide bioconjugates are constructed to form chirality-organized structures in both solid and solution states. The ferrocene serves as a reliable organometallic scaffold for the construction of protein secondary structures via intramolecular hydrogen bonding: the attached dipeptide strands are constrained within the appropriate dimensions. The introduction of the chiral dipeptide chains into the ferrocene scaffold induces the conformational enantiomerization of the ferrocenyl moiety; the chirality-organized structure results from intramolecular hydrogen bonding. The configuration and sequence of the amino acids are instrumental in the process. Regulation of the directionality and specificity of hydrogen bonding is a key component in the design of various molecular assemblies. Ferrocene-peptide bioconjugates also have a strong tendency to self-assemble through the contributions of available hydrogen-bonding donors in the solid state. Some ferrocene-peptide bioconjugates bearing only one dipeptide chain exhibit a helically ordered molecular assembly through a network of intermolecular (rather than intramolecular) hydrogen bonds. The propensity to form the chiral helicity appears to be controlled by the chirality of the dipeptide chains. Organization of host molecules is a useful strategy for forming artificial receptors. The conformationally regulated ferrocene-peptide bioconjugate provides the chirality-organized binding site for size-selective and chiral recognition of dicarboxylic acids through multipoint hydrogen bonds. Metal ions serve a variety of purposes in proteins, including structural stabilization for biological function. The complexation of ferrocene-peptide bioconjugates with palladium(II) compounds not only stabilizes the chirality conformational regulation but also induces conformational regulation of the dipeptide chain through complexation and intramolecular chirality organization. Construction of the chirality-organized ferrocene-peptide bioconjugates is also achieved by metal-directed assembly. These varied examples amply demonstrate the value of ferrocene-peptide bioconjugates in asserting architectural control over highly ordered molecular assemblies.

生物有機金属化学におけるペプチド共役分子の不斉構造制御

Ferrocene–peptide bioconjugates and urea–peptide bioconjugates are designed to induce chirality–organized structures in both solid and solution states. The ferrocene organometallic scaffold is found to serve as a reliable central reverse–turn unit for the construction of protein secondary structures via intramolecular hydrogen bonding, wherein the attached dipeptide strands are regulated in the appropriate dimensions. The configuration and sequence of the amino acids play an important role in the construction of the chirality–organized bio–inspired systems under controlled hydrogen bonding. Another noteworthy feature of ferrocene–peptide bioconjugates is their strong tendency to self–assemble through contribution of available hydrogen bonding donors in a solid state. Also, the complexation of ferrocene–peptide bioconjugates with palladium (II) compounds is demonstrated not only to stabilize the chirality conformational regulation but also to induce conformational regulation of the dipeptide chain through complexation and chirality organization based on intramolecular hydrogen bonding. Introduction of two dipeptide chains bearing the C–terminal pyridyl moiety (–L–Ala–L–Pro–NH–2–Py) into the urea scaffold is performed to form a hydrogen–bonded duplex, wherein a shuttle–like molecular dynamics based on recombination of the hydrogen bonds is observed in a solution state.