Monohydroxylated poly(3-hydroxyoctanoate) oligomers and its functionalized derivatives used as macroinitiators in the synthesis of degradable diblock copolyesters

The presence of a hydroxyl group at the end of poly(3-hydroxyoctanoate) oligomers, noted PHO oligomers, is required to prepare diblock copolymers with improved properties by ring-opening polymerization of cyclic monomer as epsilon-caprolactone. Several chemical methods such as basic hydrolysis, acid-catalyzed reaction with APTS, and methanolysis were used to prepare well-defined low molar masses PHO oligomers. The methanolysis reaction was allowed to proceed for 10-60 min to produce PHO oligomers with Mn values ranging from 20,000 to 800 g mol-1 with low polydispersity index. Detailed analysis of the MALDI-TOF mass spectra of the obtained oligomers has revealed the presence of linear structures bearing methyl ester on one side and hydroxyl end group on the other side. The same procedure was applied to poly(3-hydroxyoctanoate-co-3-hydroxyundecenoate), PHOU, a poly(3-hydroxyalkanoate) containing unsaturated units in its side chains. These oligomers were further used to initiate the polymerization of epsilon-caprolactone by varying the PHO (or PHOU) and PCL lengths. By copolymerization with epsilon-caprolactone, the properties of PHO or PHOU have been improved. The crystallinity of the obtained copolymers was modified by controlling the length of the two different blocks. The unsaturations in the side chains of the PHOU block were oxidized in acid carboxylic functions to obtain a novel artificial biopolyester. Moreover, degradation was followed to study the influence of carboxylic groups on the hydrolysis of the copolymers.     

Evidence for the 3 10-helical structure of peptides based on antAib, a fluorophoric, anthracene-fused, 1-aminocyclopentane-1-carboxylic acid

Peptides based on 2-amino-2,3-dihydro-1H-cyclopenta[b]anthracene-2-carboxylic acid (antAib), a fluorescent, achiral, alpha-amino acid belonging to the class of C(i) (alpha)-->C(i) (alpha) cyclized, C(alpha,alpha)-disubstituted glycines, combined with L-Ala, up to the hexamer level, were synthesized by solution methods and chemically characterized. A conformational analysis by FTIR absorption and NMR techniques suggests that the highest oligomers of this series tend to fold into beta-turns/3(10)-helices. The UV absorption, CD, and fluorescence properties of these antAib/L-Ala model peptides are also described.     

Oligomers of bacteriochlorophyll and bacteriopheophytin with spectroscopic properties resembling those found in photosynthetic bacteria

Oligomers of bacteriopheophytin (BPh) and bacteriochlorophyll (BChl) were formed in mixed aqueous-organic solvent systems, and in aqueous micelles of the detergent lauryldimethylamine oxide (LDAO). Conditions were found that gave relatively homogeneous samples of oligomers and that allowed quantitative comparisons of the spectroscopic properties of the monomeric and oligomeric pigments. The formation of certain types of oligomers is accompanied by a large bathochromic shift of the long-wavelength (Q_y) absorption band of the BChl or BPh, and by a substantial increase in its dipole strength (hyperchromism). The hyperchromism of the Q_y band occurs at the expense of the Soret band, which loses dipole strength. The Q_x band shifts slightly to shorter wavelengths and also loses dipole strength. The CD spectrum in the near-infra-red (Q_y) region becomes markedly nonconservative. (The net rotational strength in the Q_y region is positive.) This also occurs at the expense of the bands at shorter wavelengths, which gain a net negative rotational strength. The spectroscopic properties of the oligomers resemble those of some of the BChl-protein complexes found in photosynthetic bacteria. The oligomerization of BPh in LDAO micelles is linked to the formation of large, cylindrical micelles that contain on the order of 10⁵ LDAO molecules. However, the spectral changes probably occur on the formation of small oligomers of BPh; they begin to be seen when the micelles contain about 10 molecules of BPh. The BPh oligomers formed in LDAO micelles fluoresce at 865 nm, but the fluorescence yield is decreased about 40-fold, relative to that of monomeric BPh. The fluorescence yield is insensitive to the BPh/LDAO molar ratio, suggesting that the oligomers formed under these conditions are predominantly dimers. When the oligomers are excited with a short flash of light, they are converted with a low quantum yield into a metastable form. This transformation probably involves alterations in the geometry of the oligomer, but not full dissociation.     

Aggregation of eumelanin mitigates photogeneration of reactive oxygen species

Melanins protect tissue by absorption and rapid nonradiative, nonreactive dissipation of ultraviolet (UV) light. However, melanins also produce reactive oxygen species (ROS) upon UV illumination. A chemical understanding of this dichotomy of photoprotection and phototoxicity has not been established. Herein this issue is examined by studying the UV-B induced oxidation and reduction of cytochrome c by ROS generated by different aggregation states of eumelanin. The quantum yield for superoxide anion by unaggregated oligomers is 7.4 x 10(-3), an order of magnitude greater than that characteristic of the bulk pigment. The quantum efficiency of hydrogen peroxide production by oligomers is 5.7 x 10(-3), and its production is attributed to reaction between superoxide anion and hydroquinone groups on eumelanin oligomers. Aggregation of oligomers results in a reduction of these quantum yields, having a significantly greater effect on the efficiency of hydrogen peroxide production. This effect is attributed to the decrease in surface concentration of hydroquinone sites upon aggregation. The effect of aggregation on the photogeneration of ROS serves to provide a foundation for the understanding of the dichotomy of photoprotective and phototoxic properties of melanin.     

Efficiency Improvement of Solution‐Processed Dithienopyrrole‐Based A‐D‐A Oligothiophene Bulk‐Heterojunction Solar Cells by Solvent Vapor Annealing

The extension of a series of dithienopyrrole containing A‐D‐A oligothiophenes for application in solution‐processed bulk heterojunction solar cells is described. Using solvent vapor annealing, power conversion efficiencies up to 6.1% are obtained. Exposure of the photoactive layer to chloroform vapor results in increased absorption and ordering of the donor:acceptor blend, as is evident from UV‐vis absorption spectroscopy, X‐ray diffraction (XRD) spectroscopy, and atomic force microscopy (AFM). The type and position of the solubilizing alkyl chains influences the dissolution, optical, and packing properties of the oligomers. However, despite subtle differences in molecular structure, all electron donors could be implemented in solar cells demonstrating power conversion efficiencies between 4.4 and 6.1%. Upon further optimization of these in‐air, processed devices, it is expected that additional improvements in photovoltaic performance can be achieved.     

Control mechanisms for transport and nonlinear optical response in organic materials: a tale of twists and barriers

Simple electronic structure models are used to address two significant challenges in organic materials chemistry, the design of chromophores for strong electro-optic response (and low-energy optical absorption), and the prediction of relative mobilities and charge injection barriers for conductive oligomers. For electro-optic response, we examine two chromophore classes where twisting around an inter-ring bond can tune the electronic structure from aromatic (zwitterionic) to quinoid (neutral). The calculated nonlinear response develops a very strong maximum (β_μ ∼ 1500 ×10⁻³⁰ esu) at twist angles near 80°. For the transport behavior, structure/function correlations are presented for three series of oligomers, based on calculations of bandwidths (as functions of geometry) and of reorganization energies. Transport type appears to be fixed less by these mobility factors than by the injection barriers. The simplest estimates for these Schottky-type barriers, using frontier orbital energies from density functional calculations, predict carrier n-type or p-type behavior remarkably well.     

Cooperativity effects in linear formaldehyde oligomers using density functional theory calculations

This work reports hydrogen bonding interaction in linear formaldehyde oligomers using density functional theory method. Many-body analysis technique has been used to study the various interactions in these oligomers and to obtain % contributions from individual many-body energy terms to the binding energies of these oligomers. Co-operativity effects are studied using different indicators viz. hydrogen bond strength, inter- and intramolecular distances, dissociation energy, dipole co-operativity, energy per hydrogen bond, excess energy and non-additive energy. All these indicators show strong positive hydrogen bond co-operativity in linear formaldehyde oligomers. The dipole moment changes from 2.51 D in monomer to 20.92 D in formaldehyde heptamer.     

Establishing structure-function relationships for eumelanin

The aggregation-dependent optical properties of eumelanin from human hair are examined. When aggregation is increased, the absorption spectrum extends to lower energy. The absorption spectra of oligomers isolated from black human hair and Sepia officinalis are comparable and are in quantitative agreement with the reported action spectra for photoinduced oxygen consumption and free-radical generation by eumelanin. The agreement between the optical properties of human hair and squid eumelanins suggests the fundamental molecular constituents of the pigments are similar and aggregation-dependent photophysical behavior is a general feature of all eumelanins.     

Nucleation of β-rich oligomers and β-barrels in the early aggregation of human islet amyloid polypeptide

The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more α-helices than β-sheets, consistent with ensemble-based experimental measurements. However, in ~4–6% independent simulations, β-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These β-rich oligomers could adopt β-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these β-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. β-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.     

Thermodynamic, spectroscopic, and equilibrium binding studies of DNA sequence context effects in six 22-base pair deoxyoligonucleotides.

Effects of different end sequences on stability, circular dichroism spectra (CD), and enzyme binding properties were investigated for six 22-base pair, non-self-complementary duplex DNA oligomers. The center sequences of these deoxyoligonucleotides have 8-14 base pairs in common and are flanked on both sides by sequences differing in context and A-T content. Temperature-induced melting transitions monitored by differential scanning calorimetry (DSC) and ultraviolet absorbance were measured for the six duplexes in buffered 115 mM Na(+) solutions. Values of the melting transition enthalpy, DeltaH(cal), and entropy, DeltaS(cal), were obtained directly from DSC experiments. Melting transition parameters, DeltaH(vH) and DeltaS(vH), were also estimated from van't Hoff analysis of optical melting curves collected as a function of DNA concentration, assuming a two-state melting transition. Melting free energies (20 degrees C) of the six DNAs evaluated from DSC experiments ranged from -18.7 to -32.7 kcal/mol. van't Hoff estimates of the free energies ranged from -18.5 to -48.0 kcal/mol. With either method, the trends in free energy as a function of sequence were identical. Equilibrium binding by BamHI restriction endonuclease to the 22-base pair DNAs was also investigated. The central eight base pairs of all six molecules, 5'-A-GGATCC-A-3', contained a BamHI recognition sequence bounded by A-T base pairs. Magnesium free binding assays were performed by titering BamHI against a constant concentration of each of the deoxyoligonucleotide substrates and analyzing reaction products by gel retardation. Binding isotherms of the total amount of bound DNA versus protein concentration were constructed which provided semiquantitative estimates of the equilibrium dissociation constants for dissociation of BamHI from the six DNA oligomers. Dissociation constants ranged from 0.5 x 10(-)(9) to 12.0 x 10(-)(9) M with corresponding binding free energies of -12.5 to -10.6 (+/-0. 1) kcal/mol. An inverse relationship is found when binding and stability are compared.     

Oligomeric Interfaces Under the Lens: Gemini

The assembly of subunits in protein oligomers is an important topic to study as a vast number of proteins exists as stable or transient oligomer and because it is a mechanism used by some protein oligomers for killing cells (e.g., perforin from the human immune system, pore-forming toxins from bacteria, phage, amoeba, protein misfolding diseases, etc.). Only a few of the amino acids that constitute a protein oligomer seem to regulate the capacity of the protein to assemble (to form interfaces), and some of these amino acids are localized at the interfaces that link the different chains. The identification of the residues of these interfaces is rather difficult. We have developed a series of programs, under the common name of Gemini, that can select the subset of the residues that is involved in the interfaces of a protein oligomer of known atomic structure, and generate a 2D interaction network (or graph) of the subset. The graphs generated for several oligomers demonstrate the accuracy of the selection of subsets that are involved in the geometrical and the chemical properties of interfaces. The results of the Gemini programs are in good agreement with those of similar programs with an advantage that Gemini programs can perform the residue selection much more rapidly. Moreover, Gemini programs can also perform on a single protein oligomer without the need of comparison partners. The graphs are extremely useful for comparative studies that would help in addressing questions not only on the sequence specificity of protein interfaces but also on the mechanism of the assembly of unrelated protein oligomers.     

Studies on the structure of HCN oligomers

The structure of the water-insoluble fraction of HCN oligomers (azulmic acid) was studied by IR, NMR, gel permeation chromatography, and chemical methods. The results show that nearly half of the nitrogen atoms contained in the oligomers are of the primary amino type and the other half are involved in -C = N- type bonding. It was found that the oligomers are easily and almost quantitatively acetylated, and the acetylated oligomers show characteristic acetyl amide IR absorption and NMR spectra. Owing to the greatly improved solubility due to acetylation, the molecular weight distribution was determined for the acetylated oligomers by gel permeation chromatography. Composite peaks were obtained ranging from 300 to 900 in molecular weight. Our results are essentially consistent with the structure proposed by Völker, but we point out there may be other possible structures also consistent with our experimental results.     

Structure, stability, and interaction of fibrin αC-domain polymers

Our previous studies revealed that in fibrinogen the αC-domains are not reactive with their ligands, suggesting that their binding sites are cryptic and become exposed upon its conversion to fibrin, in which these domains form αC polymers. On the basis of this finding, we hypothesized that polymerization of the αC-domains in fibrin results in the exposure of their binding sites and that these domains adopt the physiologically active conformation only in αC-domain polymers. To test this hypothesis, we prepared a recombinant αC region (residues Aα221-610) including the αC-domain (Aα392-610), demonstrated that it forms soluble oligomers in a concentration-dependent and reversible manner, and stabilized such oligomers by covalently cross-linking them with factor XIIIa. Cross-linked Aα221-610 oligomers were stable in solution and appeared as ordered linear, branching filaments when analyzed by electron microscopy. Spectral studies revealed that the αC-domains in such oligomers were folded into compact structures of high thermal stability with a significant amount of β-sheets. These findings indicate that cross-linked Aα221-610 oligomers are highly ordered and mimic the structure of fibrin αC polymers. The oligomers also exhibited functional properties of polymeric fibrin because, in contrast to the monomeric αC-domain, they bound tPA and plasminogen and stimulated activation of the latter by the former. Altogether, the results obtained with cross-linked Aα221-610 oligomers clarify the structure of the αC-domains in fibrin αC polymers and confirm our hypothesis that their binding sites are exposed upon polymerization. Such oligomers represent a stable, soluble model of fibrin αC polymers that can be used for further structure-function studies of fibrin αC-domains.     

Steric structure of L-proline oligopeptides. II. Far-ultraviolet absorption spectra and optical rotations of L-proline oligopeptides

The results of the measurement of the far-ultraviolet absorption spectra of L -proline oligomers in water and acetonitrile are summarized as follows. The monomer has an absorption maximum at 182.5 mμ in acetonitrile. The absorption maximum of the dimer is found at 185 mμ and a shoulder appears around 200 mμ, that is, splitting of the absorption spectrum is observed in the dimer. As the degree of polymerization increases, the position of the shoulder shifts toward the wavelength of the absorption maximum of poly-L -proline II, with an accompanying increase in intensity. We may describe the absorption peak around 203 mμ of poly-L -proline II as identical with the shoulder with an increased intensity. By measurements of optical rotatory dispersion and circular dichroic spectra, it was also confirmed that the appearance of the helical conformation commences at the tetramer. When the number of residues is five or greater, the conformation of the helical structure of poly-L -proline II seems to be completed.     

Biochemical characterization of the dissociated forms from the core antenna proteins from purple bacteria

The core light-harvesting protein from Rhodospirillum rubrum is of particular interest for studying membrane polypeptide association, as it can be reversibly dissociated in the presence of n-octyl-beta-D-glucopyranoside (betaOG) into smaller subunit forms, which exhibit dramatically blue-shifted absorption properties (Miller et al. (1987) Biochemistry 26, 5055-5062). During this dissociation/reassociation process, two main spectroscopic forms are observed, absorbing at 820 (B820) and 777 (B777) nm, respectively. By using polyacrylamide gel electrophoresis in the presence of betaOG, these forms were characterized from a biochemical point of view. B777 consist of a mixture of alpha or beta polypeptide chains, retaining their bound bacteriochlorophyll (BChl) molecules. The absorption properties of the BChl molecules bound to the monomeric polypeptides do not depend on the chemical nature of the polypeptides they are bound to. B820 is more complex and consist of equilibrium between alphabeta-containing oligomers and beta only containing dimers, all exhibiting very similar electronic absorption properties. Resonance Raman spectroscopy indicates that the binding site provided by the beta-only B820 to the BChl molecules is very similar to that provided by the alphabeta B820. This, together with the observation that the alpha polypeptide alone is unable to form B820, suggests that the local organization of the BChl molecules tightly depends on BChl-protein interactions. On the other hand, our results suggest that the affinity of the beta-BChl complexes for itself and for the alpha-BChl ones are of the same order of magnitude, the formation of heterodimeric complexes being mainly driven by the inability of alpha-BChl complexes to self-associate.     

Computational study on the structural and optoelectronic properties of a carbazole-benzothiadiazole based conjugated oligomer with various alkyl side-chain lengths

The effect of the alkyl side-chain length on the structural and optoelectronic properties of poly[N-9′-heptadecanyl-27-carbazole-alt-55-(4′,7′-di-2-thienyl-2′,1′,3′-benzothiadiazole)] (PCDTBT) conjugated oligomers have been studied by density functional theory (DFT) and time-dependent density functional theory (TD-DFT). The study was carried out by varying the length of alkyl side-chain attached to the nitrogen atom of the carbazole unit of the PCDTBT oligomers. The structural properties of the optimised oligomers were then studied by determining the bond-length alternation and dihedral angles (Φ) for various side-chain lengths. Total energy calculations for the determination of HOMO energy (E_HOMO), LUMO energy (E_LUMO), and fundamental energy gap (E_Gap) were performed using DFT at the B3LYP/6-31G(d), while the first singlet excitation energies (E_Opt) were calculated by TD-DFT also at the same level of theory. It was observed that there are no significant structural changes occurring as the alkyl chain lengths are varied. For the electronic properties, very small differences (i.e. ~0.01 eV) were observed for E_Gap and E_Opt while the exciton binding energies (E_B) were virtually the same. The results suggest that using shorter alkyl side-chains do not significantly affect the structural and optoelectronic properties of the carbazole-benzothiadiazole based polymer. The observations can aid future computational design studies of analogous systems by reducing large structures thus decreasing computational costs.     

Chemical and structural disorder in eumelanins: a possible explanation for broadband absorbance

We report the results of an experimental and theoretical study of the electronic and structural properties of a key eumelanin precursor-5,6,-dihydroxyindole-2-carboxylic acid (DHICA)-and its dimeric forms. We have used optical spectroscopy to follow the oxidative polymerization of DHICA to eumelanin and observe red shifting and broadening of the absorption spectrum as the reaction proceeds. First principles density functional theory calculations indicate that DHICA oligomers (possible reaction products of oxidative polymerization) have the gap between the highest occupied molecular orbital and the lowest unoccupied molecular orbital red-shifted gaps with respect to the monomer. Furthermore, different bonding configurations (leading to oligomers with different structures) produce a range of gaps. These experimental and theoretical results lend support to the chemical disorder model where the broadband monotonic absorption characteristic of all melanins is a consequence of the superposition of a large number of nonhomogeneously broadened Gaussian transitions associated with each of the components of a melanin ensemble. These results suggest that the traditional model of eumelanin as an amorphous organic semiconductor is not required to explain its optical properties and should be thoroughly reexamined. These results have significant implications for our understanding of the physics, chemistry, and biological function of these important biological macromolecules. Indeed, one may speculate that the robust functionality of melanins in vitro is a direct consequence of its heterogeneity, i.e., chemical disorder is a "low cost" natural resource in these systems.     

Adenosine receptor containing oligomers: their role in the control of dopamine and glutamate neurotransmission in the brain

While the G protein-coupled receptor (GPCR) oligomerization has been questioned during the last fifteen years, the existence of a multi-receptor complex involving direct receptor-receptor interactions, called receptor oligomers, begins to be widely accepted. Eventually, it has been postulated that oligomers constitute a distinct functional form of the GPCRs with essential receptorial features. Also, it has been proven, under certain circumstances, that the GPCR oligomerization phenomenon is crucial for the receptor biosynthesis, maturation, trafficking, plasma membrane diffusion, and pharmacology and signalling. Adenosine receptors are GPCRs that mediate the physiological functions of adenosine and indeed these receptors do also oligomerize. Accordingly, adenosine receptor oligomers may improve the molecular mechanism by which extracellular adenosine signals are transferred to the G proteins in the process of receptor transduction. Importantly, these adenosine receptor-containing oligomers may allow not only the control of the adenosinergic function but also the fine-tuning modulation of other neurotransmitter systems (i.e. dopaminergic and glutamatergic transmission). Overall, we underscore here recent significant developments based on adenosine receptor oligomerization that are essential for acquiring a better understanding of neurotransmission in the central nervous system under normal and pathological conditions.     

Structural Determination of Aβ25-35 Micelles by Molecular Dynamics Simulations

Amyloid-β (Aβ) peptides and other amyloidogenic proteins can form a wide range of soluble oligomers of varied morphologies at the early aggregation stage, and some of these oligomers are biologically relevant to the pathogenesis of Alzheimer's disease. Spherical micelle-like oligomers have been often observed for many different types of amyloids. Here, we report a hybrid computational approach to systematically construct, search, optimize, and rank soluble micelle-like Aβ_25-35 structures with different side-chain packings at the atomic level. Simulations reveal for the first time, to our knowledge, that two Aβ micelles with antiparallel peptide organization and distinct surface hydrophobicity display high structural stability. Stable micelles experience a slow secondary structural transition from turn to α-helix. Energetic analysis coupled with computational mutagenesis reveals that van der Waals and solvation energies play a more pronounced role in stabilizing the micelles, whereas the electrostatic energies present a stable but minor energetic contribution to peptide assemblies. Modeled Aβ micelles with shapes and dimensions similar to those of experimentally derived spherical structures also provide detailed information about the roles of structural dynamics and transition in the formation of amyloid fibrils. The strong binding affinity of our micelles to antibodies implies that micelles may be a biologically relevant species.