Prediction of Raman Optical Activity Spectra of Chiral 3‐Acetylcamphorato‐Cobalt Complexes

We examine calculated vibrational Raman optical activity (ROA) spectra of octahedral cobalt complexes containing different combinations of acetylacetonato and 3‐acetylcamphorato ligands. Starting from the Δ‐tris(acetylacetonato)cobalt(III) complex, the ROA spectra of isomers generated by successive replacement of acetylacetonato ligands by chiral (+)‐ or (?)‐3‐acetylcamphorato ligands are investigated. In this way, it is possible to assess the influence of the degree of ligand substitution, ligand chirality, and geometrical isomerism on the ROA spectra. In addition, the effect of the Λ‐configuration is studied. It is found that the ROA spectra contain features that make it possible to identify each of the isomers, demonstrating the great sensitivity of ROA spectroscopy to the chiral nature of the various complexes.     

Raman Optical Activity of a Purely σ‐Bonded Helical Chromophore: (−)‐(M)‐σ‐[4]Helicene

The recent synthesis of enantiomerically pure (−)‐(M)‐σ‐[4]helicene has provided an archetype helical model system for vibrational optical activity, comparable to what π‐helicenes represent in the field of electronic optical activity. We present the first measurements and the first calculations of the Raman optical activity (ROA) of this interesting molecule. Observed and calculated ROA is large throughout the vibrational spectrum, in agreement with expectations, and spectacular effects, with Δ values close to 0.5%, occur in the 900‐cm⁻¹ region. Agreement between the experimental spectrum and the theoretical one, calculated with density‐functional theory for the vibrational part and Hartree‐Fock linear response theory for the molecular electronic tensors, is excellent, clearly the best that has been achieved to date in the field. This allows us to place confidence in the results of an analysis of Raman and ROA scattering generation in the molecule, obtained by a newly developed graphical procedure for extracting this kind of information from ab initio calculations. One finds that relative contributions made by carbon and hydrogen atoms can be comparable in size, but can also vary considerably, even between closely lying vibrations, and that, for most vibrations, the generation of ROA difference intensity is distributed rather differently than that of Raman intensity over the shape of the molecule. The sign of the ROA is, for the set of vibrations in the 900‐cm⁻¹ region, which we analyze in detail, determined by coupling terms between the two halves of the molecule, while Raman intensity is primarily generated within the two fragments, with coupling terms between them only adding to or substracting from it.     

Poly(2‐oxazoline) hydrogels crosslinked with aliphatic bis(2‐oxazoline)s: Properties,cytotoxicity, and cell cultivation

A series of hydrogels from 2‐ethyl‐2‐oxazoline and three bis(2‐oxazoline) crosslinkers—1,4‐butylene‐2,2′‐bis(2‐oxazoline), 1,6‐hexamethylene‐2,2′‐bis(2‐oxazoline), and 1,8‐octamethylene‐2,2′‐bis(2‐oxazoline)—are prepared. The hydrogels differ by the length of aliphatic chain of crosslinker and by the percentage of crosslinker (2–10%). The influence of the type and the percentage of the crosslinker on swelling properties, mechanical properties, and state of water is studied. The equilibrium swelling degree in water ranges from 2 to 20. With a proper selection of the crosslinker, Young's modulus can be varied from 10 kPa to almost 100 kPa. To evaluate the potential for medical applications, the cytotoxicity of extracts and the contact toxicity toward murine fibroblasts are measured. The hydrogels with the crosslinker containing a shorter aliphatic exhibit low toxicity toward fibroblast cells. Moreover, the viability and the proliferation of pancreatic β‐cells incubated inside hydrogels for 12 days are analyzed. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 1548–1559     

Transfer and Amplification of Chirality Within the “Ring of Fire” Observed in Resonance Raman Optical Activity Experiments

We report extremely strong chirality transfer from a chiral nickel complex to solvent molecules detected as Raman optical activity (ROA). Electronic energies of the complex were in resonance with the excitation‐laser light. The phenomenon was observed for a wide range of achiral and chiral solvents. For chiral 2‐butanol, the induced ROA was even stronger than the natural one. The observations were related to so‐called quantum (molecular) plasmons that enable a strong chiral Rayleigh scattering of the resonating complex. According to a model presented here, the maximal induced ROA intensity occurs at a certain distance from the solute, in a three‐dimensional “ring of fire”, even after rotational averaging. Most experimental ROA signs and relative intensities could be reproduced. The effect might significantly increase the potential of ROA spectroscopy in bioimaging and sensitive detection of chiral molecules.     

Injectable supramolecular hybrid hydrogels formed by MWNT‐grafted‐poly(ethylene glycol) and α‐cyclodextrin

Poly(ethylene glycol)‐grafted‐multiwalled carbon nanotube (MWNT‐g‐PEG) was synthesized by a coupling reaction and formed inclusion complexes (ICs) after selective threading of the PEG segment of the MWNT‐g‐PEG through the cavities of α‐cyclodextrins (α‐CDs) units. The polypseudorotaxane structures of the as‐obtained hydrogels were confirmed by ¹H NMR, X‐ray diffraction and DSC analyses. The complexation of the PEG segments with α‐CDs and the hydrophobic interaction between the MWNT resulted in the formation of supramolecular hybrid hydrogels with a strong network. Thermal analysis showed that the thermal stability of the hydrogel was substantially improved by up to 100 °C higher than that of native hydrogel. The resultant hybrid hydrogels were found to be thixotropic and reversible, and could be applied as a promising injectable drug delivery system. The mechanical strength of the hybrid hydrogels was greatly improved in comparison with that of the corresponding native hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3145–3151, 2010     

New hydrogels from interpenetrated physical gels of agarose and chemical gels of polyacrylamide: Effect of relative concentration and crosslinking degree on the viscoelastic and thermal properties

In this article, we report on the viscoelastic and thermal properties of agarose–polyacrylamide (PAAm) interpenetrating polymer hydrogels (IPHs) and semi‐IPHs as a function of agarose concentration and PAAm crosslinking degree. The results demonstrated that the agarose is able to gel in the presence of crosslinked and linear IPHs. In addition, the reticulation of PAAm in the presence of agarose is confirmed for the case of IPHs giving rise to systems with dimensional stability at high temperatures. The formation of a fully IPH was ascertained at low agarose concentrations. A study of the morphology and nanoscale elasticity of the different systems has been carried out with atomic force microscopy/ultrasonic force microscopy (UFM). UFM data provide further evidence of interpenetration, allowing us to visualize—if present—phase‐separated domains with nanoscale resolution for the various crosslinking degrees and PAAm and agarose concentrations used during the formation of the IPHs. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2010     

Studying the Glycan Moiety of RNase B by Means of Raman and Raman Optical Activity

Raman and Raman optical activity (ROA) spectroscopy are used to study the solution‐phase structure of the glycan moiety of the protein ribonuclease B (RNase B). Spectral data of the intact glycan moiety of RNase B is obtained by subtracting high‐quality spectral data of RNase A, the non‐glycosylated form of the RNase, from the spectra of the glycoprotein. The remaining difference spectra are compared to spectra generated from Raman and ROA data of the constituent disaccharides of the RNase glycan, achieving convincing spectral overlap. The results show that ROA spectroscopy is able to extract detailed spectral data of the glycan moieties of proteins, provided that the non‐glycosylated isoform is available. Furthermore, good comparison between the full glycan spectrum and the regenerated spectra based on the disaccharide data lends great promise to ROA as a tool for the solution‐phase structural analysis of this structurally elusive class of biomolecules.     

Matrix Isolation‐Vibrational Circular Dichroism Spectroscopy of 3‐Butyn‐2‐ol and its Binary Aggregates

Vibrational circular dichroism (VCD) spectroscopy has a unique specificity to chirality and is highly sensitive to the conformational equilibria of chiral molecules. On the other hand, the matrix‐isolation (MI) technique allows substantial control over sample compositions, such as the sample(s)/matrix ratio and the ratio among different samples, and yields spectra with very narrow bandwidths. We combined VCD spectroscopy with the MI technique to record MI‐VCD and MI‐vibrational absorption spectra of 3‐butyn‐2‐ol at different MI temperatures, which allowed us to investigate the conformational distributions of its monomeric and binary species. Good mirror‐imaged MI‐VCD spectra of opposite enantiomers were achieved. The related conformational searches were performed for the monomer and the binary aggregate and their vibrational absorption and VCD spectra were simulated. The well‐resolved experimental MI‐VCD bands provide the essential mean to assign the associated vibrational absorption spectral features correctly to a particular conformation in case of closely spaced bands. By varying the matrix temperature, we show that one can follow the self‐aggregation process of 3‐butyn‐2‐ol and confidently correlate the MI‐VCD spectral features with those obtained for a 0.1 M CCl₄ solution and as a neat liquid at room temperature. Comparison of the aforementioned experimental VCD spectra shows conclusively that there is a substantial contribution from the 3‐butyn‐2‐ol aggregate even at 0.1 M concentration. This spectroscopic combination will be powerful for studying self‐aggregation of chiral molecules, and chirality transfer from a chiral molecule to an interacting achiral molecule and in electron donor–acceptor chiral complexes.     

Computational Interpretation of Vibrational Optical Activity: The ROA Spectra of (4S)‐4‐Methylisochromane and the (4S)‐Isomers of Galaxolide®

The reliable computation of Raman‐optical‐activity (ROA) spectra of molecules of the size of the title compounds has, until now, not been possible. We show that our rarefied basis sets yield results in good agreement with the experimental data for (4S)‐4‐methylisochromane (=(4S)‐3,4‐dihydro‐4‐methyl‐1H‐2‐benzopyran; 1 ), provided the equilibrium between the pseudo‐equatorial and the pseudo‐axial conformers is taken into account. Comparison between the measured and the computed ROA back‐scattering spectra allows the unequivocal assignment of the absolute configuration of the molecule. Comparison with more‐approximate calculations for the larger (4S)‐isomers of Galaxolide^® ( 2 ), which contain the (4S)‐4‐methylisochromane moiety, shows large‐scale group frequencies on the same chiral fragments of the two molecules. The data confirm that ROA can be generated by interactions extending over several bonds, i.e., over larger distances than can be probed by NMR spectroscopy. Thus, the absolute configuration at C(7) of Galaxolide^® is assignable independently of that at C(4). The computation of ROA for forward‐scattering, which will soon be measurable for Galaxolide^®, suggests that this scattering geometry provides additional stereochemical information that will be valuable in situations where absolute configurations at several stereogenic centers have to be assigned.     

Intermolecular Hydrogen Bonding and Structures in 1,3‐Dioxane/D2O Mixtures Studied by High‐Pressure Raman Spectroscopy

The ability of the equatorial C‐H bonds to form C‐H—O hydrogen bonds was studied by measuring the high‐pressure Raman spectra. We have investigated the effect of pressure versus C‐H—O interactions in 1,3‐dioxane/D₂O mixtures. Dilution of 1,3‐dioxane leads to a shift of the C‐H signals to higher frequencies under ambient pressure. Based on the pressure‐dependence of the Raman spectra, we have found that the equatorial C‐H groups of 1,3‐dioxane displays a remarkably different ability to serve as the weak hydrogen bond donors in comparison to the axial C‐H of 1,3‐dioxane. The new Raman spectral features observed under high pressure may arise from the combined effect of hydrogen‐bond network changes, hydrogen bond‐like C‐H—O interactions formation, cluster size changes, etc. This finding may be important to diastereo‐ and enantioselective synthesis.     

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

Oligopeptide‐based supramolecular hydrogels hold promise in a range of applications. The gelation of these systems is hard to control, with minor alterations in the peptide sequence significantly influencing the self‐assembly process. We explored three pentapeptide sequences with different charge distributions and discovered that they formed robust, pH‐responsive hydrogels. By altering the concentration and charge distribution of the peptide sequence, the stiffness of the hydrogels could be tuned across two orders of magnitude (2–200 kPa). Also, through reassembly of the β‐sheet interactions the hydrogels could self‐heal and they demonstrated shear‐thin behavior. Using spectroscopic and cryo‐imaging techniques, we investigated the relationship between peptide sequence and molecular structure, and how these influence the mechanical properties of the hydrogel. These pentapeptide hydrogels with tunable morphology and mechanical properties have promise in tissue engineering, injectable delivery vectors, and 3D printing applications.     

A comparative study of two polymorphs of bis(1‐hydroxy‐2‐methylpropan‐2‐aminium) carbonate

Alkanolamines have been known for their high CO₂ absorption for over 60 years and are used widely in the natural gas industry for reversible CO₂ capture. In an attempt to crystallize a salt of (RS)‐2‐(3‐benzoylphenyl)propionic acid with 2‐amino‐2‐methylpropan‐1‐ol, we obtained instead a polymorph (denoted polymorph II) of bis(1‐hydroxy‐2‐methylpropan‐2‐aminium) carbonate, 2C₄H₁₂NO⁺·CO₃²⁻, (I), suggesting that the amine group of the former compound captured CO₂ from the atmosphere forming the aminium carbonate salt. This new polymorph was characterized by single‐crystal X‐ray diffraction analysis at low temperature (100 K). The salt crystallizes in the monoclinic system (space group C2/c, Z = 4), while a previously reported form of the same salt (denoted polymorph I) crystallizes in the triclinic system (space group P, Z = 2) [Barzagli et al. (2012). ChemSusChem, 5 , 1724–1731]. The asymmetric unit of polymorph II contains one 1‐hydroxy‐2‐methylpropan‐2‐aminium cation and half a carbonate anion, located on a twofold axis, while the asymmetric unit of polymorph I contains two cations and one anion. These polymorphs exhibit similar structural features in their three‐dimensional packing. Indeed, similar layers of an alternating cation–anion–cation neutral structure are observed in their molecular arrangements. Within each layer, carbonate anions and 1‐hydroxy‐2‐methylpropan‐2‐aminium cations form planes bound to each other through N—H…O and O—H…O hydrogen bonds. In both polymorphs, the layers are linked to each other via van der Waals interactions and C—H…O contacts. In polymorph II, a highly directional C—H…O contact (C—H…O = 156°) shows as a hydrogen‐bonding interaction. Periodic theoretical density functional theory (DFT) calculations indicate that both polymorphs present very similar stabilities.     

Resonance Raman optical activity and surface enhanced resonance Raman optical activity analysis of cytochrome c

High-resolution resonance Raman (RR) and resonance Raman optical activity (ROA) spectra of cytochrome c were obtained in order to perform full assignment of spectral features of the resonance ROA spectrum. The resonance ROA spectrum of cytochrome c revealed a distinct spectral signature pattern due to resonance enhanced skeletal porphyrin vibrations, more pronounced than any contribution from the protein backbone. Combining the intrinsic resonance properties of cytochrome c with the surface plasmon enhancement achieved with colloidal silver particles, the surface enhanced resonance Raman scattering (SERRS) and surface enhanced resonance ROA (SERROA) spectra of the protein were successfully obtained at concentrations as low as 1 microM. The assignments of spectral features were based on the information obtained from the RR and resonance ROA spectra. Excellent agreement between RR and SERRS spectra is reported, while some disparities were observed between the resonance ROA and SERROA spectra. These differences can be ascribed to perturbations of the physical properties of the protein upon adhesion to the surface of the silver colloids.     

Cold Denaturation of α‐Synuclein Amyloid Fibrils

Although amyloid fibrils are associated with numerous pathologies, their conformational stability remains largely unclear. Herein, we probe the thermal stability of various amyloid fibrils. α‐Synuclein fibrils cold‐denatured to monomers at 0–20 °C and heat‐denatured at 60–110 °C. Meanwhile, the fibrils of β2‐microglobulin, Alzheimer’s Aβ1‐40/Aβ1‐42 peptides, and insulin exhibited only heat denaturation, although they showed a decrease in stability at low temperature. A comparison of structural parameters with positive enthalpy and heat capacity changes which showed opposite signs to protein folding suggested that the burial of charged residues in fibril cores contributed to the cold denaturation of α‐synuclein fibrils. We propose that although cold‐denaturation is common to both native proteins and misfolded fibrillar states, the main‐chain dominated amyloid structures may explain amyloid‐specific cold denaturation arising from the unfavorable burial of charged side‐chains in fibril cores.     

Synthesis and characterization of temperature‐ and pH‐sensitive hydrogels based on poly(2‐ethyl‐2‐oxazoline) and poly(D,L‐lactide)

A novel series of temperature‐ and pH‐sensitive hydrogels based on poly(2‐ethyl‐2‐oxazoline) and three‐arm poly(D,L ‐lactide) were synthesized via photocopolymerization. For the creation of polymeric networks, two types of macromers terminated with methacrylate groups were prepared: poly(2‐ethyl‐2‐oxazoline) dimethacrylate and three‐arm poly(D,L ‐lactide) trimethacrylate. The chemical structures were analyzed with ¹H NMR and Fourier transform infrared techniques. The thermal behaviors, morphologies, and swelling properties were measured for the characterization of the polymeric networks. All the poly(2‐ethyl‐2‐oxazoline)/three‐arm poly(D,L ‐lactide)hydrogels provided high water retention capacity and exhibited reversible swelling–shrinking behavior in response to temperature and pH variations. The hydrogels with higher poly(2‐ethyl‐2‐oxazoline) dimethacrylate contents were more effective in raising the swelling ratio and temperature and pH sensitivity. However, higher contents of three‐arm poly(D,L ‐lactide) trimethacrylate produced larger particles and pore sizes in the hydrogels. This study effectively proves that this unique combination of water swellability and biodegradability provides hydrogels with a much wider range of applications in biomedical fields. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1112–1121, 2002     

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

Self‐healing supramolecular hydrogels have emerged as a novel class of biomaterials that combine hydrogels with supramolecular chemistry to develop highly functional biomaterials with advantages including native tissue mimicry, biocompatibility, and injectability. These properties are endowed by the reversibly cross‐linked polymer network of the hydrogel. These hydrogels have great potential for realizing yet to be clinically translated tissue engineering therapies. This review presents methods of self‐healing supramolecular hydrogel formation and their uses in tissue engineering as well as future perspectives.     

Synthesis of 3‐(substituted)‐2,4,8,15‐tetroxa‐3‐phosphadispiro[5.2.5]hexadecane‐3‐oxides

Novel 3‐(substituted)‐2,4,8,15‐tetroxa‐3‐phosphadispiro[5.2.5]hexadecane‐3‐oxides (3‐12) have been synthesized by cyclization of 1,5‐dioxaspiro[5.5]undecande‐3,3‐dimethanol (1) with various substituted aryl phosphorus dichloridates (2) in dry toluene‐THF in the presence of triethylamine at 40‐60 ^oC. Their molecular structures were determined by ir, nmr and mass spectral studies and were screened for antifungal activity against Curvularia lunata and Aspergillus niger, and antibacterial activity on Staphylococcus aureus and Escherichia coli. Most of them possess significant activity.     

Silk‐Inspired β‐Peptide Materials Resist Fouling and the Foreign‐Body Response

The functions of implants like medical devices are often compromised by the host's foreign‐body response (FBR). Herein, we report the development of low‐FBR materials inspired by serine‐rich sericin from silk. Poly‐β‐homoserine (β‐HS) materials consist of the hydrophilic unnatural amino acid β‐homoserine. Self‐assembled monolayers (SAMs) of β‐HS resist adsorption by diverse proteins, as well as adhesion by cells, platelets, and diverse microbes. Experiments lasting up to 3 months revealed that, while implantation with control PEG hydrogels induced obvious inflammatory responses, collagen encapsulation, and macrophage accumulation, these responses were minimal with β‐HS hydrogels. Strikingly, the β‐HS hydrogels induce angiogenesis in implant‐adjacent tissues. Molecular dynamics simulations indicated that the low FBR performance of β‐HS results from what we term “dual hydrogen bonding hydration”, wherein both the backbone amide groups and the sidechain hydroxyl groups of β‐HS undergo hydration.     

Micelle‐Triggered β‐Hairpin to α‐Helix Transition in a 14‐Residue Peptide from a Choline‐Binding Repeat of the Pneumococcal Autolysin LytA

Choline‐binding modules (CBMs) have a ββ‐solenoid structure composed of choline‐binding repeats (CBR), which consist of a β‐hairpin followed by a short linker. To find minimal peptides that are able to maintain the CBR native structure and to evaluate their remaining choline‐binding ability, we have analysed the third β‐hairpin of the CBM from the pneumococcal LytA autolysin. Circular dichroism and NMR data reveal that this peptide forms a highly stable native‐like β‐hairpin both in aqueous solution and in the presence of trifluoroethanol, but, strikingly, the peptide structure is a stable amphipathic α‐helix in both zwitterionic (dodecylphosphocholine) and anionic (sodium dodecylsulfate) detergent micelles, as well as in small unilamellar vesicles. This β‐hairpin to α‐helix conversion is reversible. Given that the β‐hairpin and α‐helix differ greatly in the distribution of hydrophobic and hydrophilic side chains, we propose that the amphipathicity is a requirement for a peptide structure to interact and to be stable in micelles or lipid vesicles. To our knowledge, this “chameleonic” behaviour is the only described case of a micelle‐induced structural transition between two ordered peptide structures.     

The Influence of the Amino Acid Side Chains on the Raman Optical Activity Spectra of Proteins

The Raman optical activity (ROA) spectra of proteins show distinct patterns arising from the secondary structure. It is generally believed that the spectral contributions of the side-chains largely cancel out because of their flexibility and the occurrence of many side-chains with different conformations. Yet, the influence of the side-chains on the ROA patterns assigned to different secondary structures is unknown. Here, the first systematic study of the influence of all amino acid side-chains on the ROA patterns is presented based on density functional theory (DFT) calculations of an extensive collection of peptide models that include many different side-chain and secondary structure conformations. It was shown that the contributions of the side-chains to a large extent average out with conformational flexibility. However, specific side-chain conformations can have significant contributions to the ROA patterns. It was also shown that α-helical structure is very sensitive to both the exact backbone conformation and the side-chain conformation. Side-chains with χ₁≈−60° generate ROA patterns alike those in experiment. Aromatic side-chains strongly influence the amide III ROA patterns. Because of the huge structural sensitivity of ROA, the spectral patterns of proteins arise from extensive conformational averaging of both the backbone and the side-chains. The averaging results in the fine spectral details and relative intensity differences observed in experimental spectra.