Determination of the absolute configuration (AC) is often a challenging aspect in the structure elucidation of natural products. When chiral compounds possess appropriate chromophore(s), electronic circular dichroism (ECD) may provide a powerful approach to the determination of their absolute configuration. Recently, ECD calculations by time-dependent density functional theory (TDDFT) have come to be used more commonly. In the present review, we give several examples of recent studies using TDDFT-calculated ECD spectra for the AC determination of natural products.

The Nucleic Acid Circular Dichroism Database (NACDDB) is a public repository that archives and freely distributes circular dichroism (CD) and synchrotron radiation CD (SRCD) spectral data about nucleic acids, and the associated experimental metadata, structural models, and links to literature. NACDDB covers CD data for various nucleic acid molecules, including DNA, RNA, DNA/RNA hybrids, and various nucleic acid derivatives. The entries are linked to primary sequence and experimental structural data, as well as to the literature. Additionally, for all entries, 3D structure models are provided. All entries undergo expert validation and curation procedures to ensure completeness, consistency, and quality of the data included. The NACDDB is open for submission of the CD data for nucleic acids. NACDDB is available at: https://genesilico.pl/nacddb/.

Understanding the chirality of molecular reaction pathways is essential for a broad range of fundamental and applied sciences. However, the current ability to probe chirality on the time scale of primary processes underlying chemical reactions remains very limited. Here, we demonstrate time-resolved photoelectron circular dichroism (TRPECD) with ultrashort circularly polarized vacuum-ultraviolet (VUV) pulses from a tabletop source. We demonstrate the capabilities of VUV-TRPECD by resolving the chirality changes in time during the photodissociation of atomic iodine from two chiral molecules. We identify several general key features of TRPECD, which include the ability to probe dynamical chirality along the complete photochemical reaction path, the sensitivity to the local chirality of the evolving scattering potential, and the influence of electron scattering off dissociating photofragments. Our results are interpreted by comparison with high-level ab-initio calculations of transient PECDs from molecular photoionization calculations. Our experimental and theoretical techniques define a general approach to femtochirality.

No abstract available

The observation of circular dichroism (CD) in vibrational transitions in the infrared spectral region offers new possibilities for the determination of peptide solution conformation. Infrared or vibrational CD (VCD) is a particularly sensitive probe for the conformation of various peptide turns. Results of small linear and cyclic peptides containing beta- or gamma-turns are reported.

An achiral chromophore can acquire a chiral spectroscopic signature when interacting with a chiral environment. This so-called induced chirality is documented in electronic or vibrational circular dichroism, which arises from the coupling between electric and magnetic transition dipoles. Here, we demonstrate that a chiroptical response is also induced within the electric dipole approximation by observing the asymmetric scattering of a photoelectron ejected from an achiral chromophore in interaction with a chiral host. In a phenol-methyloxirane complex, removing an electron from an achiral aromatic π orbital localised on the phenol moiety results in an intense and opposite photoelectron circular dichroism (PECD) for the two enantiomeric complexes with (R) and (S) methyloxirane, evidencing the long-range effect (~5 Å) of the scattering chiral potential. This induced chirality has important structural and analytical implications, discussed here in the context of growing interest in laser-based PECD, for in situ, real time enantiomer determination.

Ultraviolet (UV) synchrotron radiation circular dichroism (SRCD) spectroscopy has made an important contribution to the determination and understanding of the structure of bio-molecules. In this paper, we report an innovative approach that we term time-resolved SRCD (tr-SRCD), which overcomes the limitations of current broadband UV SRCD setups. This technique allows accessing ultrafast time scales (down to nanoseconds), previously measurable only by other methods, such as infrared (IR), nuclear magnetic resonance (NMR), fluorescence and absorbance spectroscopies, and small angle X-ray scattering (SAXS). The tr-SRCD setup takes advantage of the natural polarization of the synchrotron radiation emitted by a bending magnet to record broadband UV CD faster than any current SRCD setup, improving the acquisition speed from 10 mHz to 130 Hz and the accessible temporal resolution by several orders of magnitude. We illustrate the new approach by following the isomer concentration changes of an azopeptide after a photoisomerization. This breakthrough in SRCD spectroscopy opens up a wide range of potential applications to the detailed characterization of biological processes, such as protein folding and protein-ligand binding.

The flexibility of a molecule has important consequences on its function and application. Vibrational Circular Dichroism (VCD) is intrinsically an excellent experimental technique to get a hold on this flexibility as it is highly sensitive to key conformational details and able to distinguish rapidly interconverting conformers. One of the major challenges in analyzing the spectra by comparison to theoretical predictions is the uncertainty in the computed energies of the multitude of conformations. This uncertainty also affects the reliability of the stereochemical assignment it is normally used for. We present here a novel approach that explicitly takes the energy uncertainties into account in a genetic algorithm based method that fits calculated to the experimental spectra. We show that this approach leads to significant improvements over previously used methodologies. Importantly, statistical validation studies provide quantitative measures for the reliability of relevant parameters used such as the energy uncertainty and the extent to which conformational heterogeneity can be determined. Similarly, quantitative measures can be obtained for the possibility that the flexibility that is introduced in the fit might lead to an incorrect assignment of the stereochemistry. These results break new ground for different techniques based on VCD to elucidate conformational flexibility.

Circular dichroism (CD) spectroscopy has been widely demonstrated for detecting chiral molecules. However, the determination of chiral mixtures with various concentrations and enantiomeric ratios can be a challenging task. To solve this problem, we report an enhanced vibrational circular dichroism (VCD) sensing platform based on plasmonic chiral metamaterials, which presents a 6-magnitude signal enhancement with a selectivity of chiral molecules. Guided by coupled-mode theory, we leverage both in-plane and out-of-plane symmetry-breaking structures for chiral metamaterial design enabled by a two-step lithography process, which increases the near-field coupling strengths and varies the ratio between absorption and radiation loss, resulting in improved chiral light-matter interaction and enhanced molecular VCD signals. Besides, we demonstrate the thin-film sensing process of BSA and β-lactoglobulin proteins, which contain secondary structures α-helix and β-sheet and achieve a limit of detection down to zeptomole level. Furthermore, we also, for the first time, explore the potential of enhanced VCD spectroscopy by demonstrating a selective sensing process of chiral mixtures, where the mixing ratio can be successfully differentiated with our proposed chiral metamaterials. Our findings improve the sensing signal of molecules and expand the extractable information, paving the way toward label-free, compact, small-volume chiral molecule detection for stereochemical and clinical diagnosis applications.

The neuropeptides orexin A and B regulate various vital functions of the body, such as sleep/wake states, metabolism, and energy homeostasis. A loss of their physiological activity, with reduced ability to recognize their receptors, is suspected to be associated with oxidative stress conditions. These are related to excessive presence of reactive oxygen and nitrogen species, as well as of reactive lipoxidation byproducts. With the aim of evaluating the effects of oxidative stress on the secondary structure of orexin peptides, orexin B was synthesized and characterized by circular dichroism spectroscopy under different conditions. In aqueous solution it presents an unordered conformation, while in a membrane mimetic environment it assumes a helical structure. The effects of oxidative stress were evaluated exposing it to both oxygen and nitrogen radicals as well as to lipoxidation byproducts. The results showed that ROS, but not NRS, induced appreciable conformational changes, and only in the membrane mimetic environment. Lipoxidation byproducts, instead, led to secondary structure modifications much more evident than those induced by the direct action of ROS and RNS, and in both analyzed media. Additionally, MALDI-TOF analyses detected mass variations in the peptide attributable to oxidation of the C-terminal Met residue and deamination of asparagine in the Asn-His sequence. Taken together, all these data seem to confirm the involvement of oxidative processes in dysfunctions of the orexinergic system.

No abstract available

Molecular chirality and the inherently connected differential absorption of circular polarized light (CD) combined with semiconducting properties offers great potential for chiral opto-electronics. Here we discuss the temperature-controlled assembly of enantiopure prolinol functionalized squaraines with opposite handedness into intrinsically circular dichroic, molecular J-aggregates in spincasted thin films. By Mueller matrix spectroscopy we accurately probe an extraordinary high excitonic circular dichroism, which is not amplified by mesoscopic ordering effects. At maximum, CD values of 1000 mdeg/nm are reached and, after accounting for reflection losses related to the thin film nature, we obtain a film thickness independent dissymmetry factor g = 0.75. The large oscillator strength of the corresponding absorption within the deep-red spectral range translates into a negative real part of the dielectric function in the spectral vicinity of the exciton resonance. Thereby, we provide a new small molecular benchmark material for the development of organic thin film based chiroptics.

Calprotectin (CP) is an abundant metal-chelating protein involved in host defense, and the ability of human CP to bind Fe(ii) in a calcium-dependent manner was recently discovered. In the present study, near-infrared magnetic circular dichroism spectroscopy is employed to investigate the nature of Fe(ii) coordination at the two transition-metal-binding sites of CP that are a His3Asp motif (site 1) and a His6 motif (site 2). Upon the addition of sub-stoichiometric Fe(ii), a six-coordinate (6C) Fe(ii) center associated with site 2 is preferentially formed in the presence of excess Ca(ii). This site exhibits an exceptionally large ligand field (10Dq = 11 045 cm-1) for a non-heme Fe(ii) protein. Analysis of CP variants lacking residues of the His6 motif supports that CP coordinates Fe(ii) at site 2 by employing six His ligands. In the presence of greater than one equiv. of Fe(ii) or upon mutation of the His6 motif, the metal ion also binds at site 1 of CP to form a five-coordinate (5C) Fe(ii)-His3Asp motif that was previously unidentified in this system. Notably, the introduction of His-to-Ala mutations at the His6 motif results in a mixture of 6C (site 2) and 5C (site 1) signals in the presence of sub-stoichiometric Fe(ii). These results are consistent with a reduced Fe(ii)-binding affinity of site 2 as more weakly coordinating water-derived ligands complete the 6C site. In the absence of Ca(ii), both sites 1 and 2 are occupied upon addition of sub-stoichiometric Fe(ii), and a stronger ligand field is observed for the 5C site. These spectroscopic studies provide further evaluation of a unique non-heme Fe(ii)-His6 site for metalloproteins and support the notion that Ca(ii) ions influence the Fe(ii)-binding properties of CP.

The development of peptidomimetic foldamers that can form well-defined folded structures is highly desirable yet challenging. We previously reported on α-ABpeptoids, oligomers of N-alkylated β²-homoalanines and found that due to the presence of chiral methyl groups at α-positions, α-ABpeptoids were shown to adopt folding conformations. Here, we report β-ABpeptoids having chiral methyl group at β-positions rather than α-positions as a different class of peptoids with backbone chirality. We developed a facile solid-phase synthetic route that enables the synthesis of β-ABpeptoid oligomers ranging from 2-mer to 8-mer in excellent yields. These oligomers were shown to adopt ordered folding conformations based on circular dichroism (CD) and NMR studies. Overall, these results suggest that β-ABpeptoids represent a novel class of peptidomimetic foldamers that will find a wide range of applications in biomedical and material sciences.

Over recent years, quantum dots (QDs) based on ternary metal dichalcogenides have attracted a lot of attention due to their unique properties and a range of potential applications. Here, we review the latest studies on the optical properties of AgInS2/ZnS QDs with emphasis on their theoretical modeling, and present our investigations of electronic transitions invisible in unstructured absorption spectra of AgInS2/ZnS QDs. The analysis of the absorption, photoluminescence excitation (PLE), and magnetic circular dichroism (MCD) spectra of hydrophobic and hydrophilic AgInS2/ZnS QDs of different sizes enables us to determine positions of electron transitions in these QDs. We demonstrate that the use of the second derivative of PLE spectra provides more unequivocal data on the position of the energy transitions compared with the second derivative of absorption spectra. Analysis of the MCD spectra reveals that the magnetic field induces energy level mixing in AgInS2/ZnS QDs in contrast to the traditional Cd-based QDs, where MCD is associated only with removing degeneracy of the excited energy level.

Tolterodine (1) is a potent muscarinic receptor antagonist used in the treatment of overactive urinary bladder (OAB) syndrome. Tolterodine is chiral and it was patented, and is currently marketed, as the l-tartrate salt of the (R)-enantiomer. However, the existing literature does not offer an ultimate proof of a stereoselective mode of action of 1. A second open stereochemical issue concerns the absolute configuration (AC) of 1. Neither the original patents nor subsequent studies have established the AC of 1 in an unambiguous way, although the AC of the l-tartrate salt of 1 was assigned by X-ray diffractometry. Finally, neither electronic nor vibrational circular dichroism (ECD and VCD) spectra of 1 are reported so far. We performed a thorough ECD/VCD study of 1 in different solvents and at variable temperatures. Solvent and temperature dependence highlighted the existence of moderate flexibility which was confirmed by molecular modelling. ECD calculations with time-dependent density functional theory (TDDFT) accurately reproduced the experimental spectra and allowed us to confirm the AC of 1 in an independent way.

A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper insights into biophysical and simulation studies of protein dynamics and folding. In contrast to intense bands in the far-ultraviolet, near-UV bands are much weaker and have been challenging to compute theoretically. We report some advances in the accuracy of calculations in the near-UV, which were realised through the consideration of the vibrational structure of the electronic transitions of aromatic side chains.

Intrinsically disordered proteins (IDPs) are comprised of significant numbers of residues that form neither helix, sheet, nor any other canonical type of secondary structure. They play important roles in a broad range of biological processes, such as molecular recognition and signalling, largely due to their chameleon-like ability to change structure from unordered when free in solution to ordered when bound to partner molecules. Circular dichroism (CD) spectroscopy is a widely-used method for characterising protein secondary structures, but analyses of IDPs using CD spectroscopy have suffered because the methods and reference datasets used for the empirical determination of secondary structures do not contain adequate representations of unordered structures. This work describes the creation, validation and testing of a standalone Windows-based application, DichroIDP, and a new reference dataset, IDP175, which is suitable for analyses of proteins containing significant amounts of disordered structure. DichroIDP enables secondary structure determinations of IDPs and proteins containing intrinsically disordered regions.

Vibrational circular dichroism (VCD) spectra in the OH- and NH-stretching regions have been measured for six pharmaceutical molecules in the ephedra class, (1S,2R)-norephedrine, (1), (1S,2S)-norpseudoephedrine (2), (1S,2R)-ephedrine (3), (1S,2S)-pseudoephedrine (4), (1S,2R)-N-methylephedrine (5) and (1S,2S)-N-methylpseudoephedrine (6), all in dilute C2Cl4 solution. Ab initio calculations of geometries and vibrational frequencies for a number of conformers of 1 to 6 have been carried out. The recently developed locally distributed origin gauge model for VCD was used to calculate VCD spectra of the conformers for each drug. This ground-state ab initio model, which does not require sum-over-states, magnetic field perturbation or localized molecular orbitals, has been found to give good agreement with experiment in this frequency region. Composite spectra obtained from weighted averages of the calculated conformer spectra agree within a factor of two with observed IR and VCD intensities for five of the ephedra drugs. For (1S,2S)-pseudoephedrine, the discrepancy between experiment and calculation has been interpreted in terms of a coupled-oscillator effect absent in the other molecules.

Circular dichroism (CD) spectroscopy is a widely-used method in biochemistry, structural biology and pharmaceutical chemistry. More than 24 000 papers published in the past decade have included CD characterisations of proteins; many of those studies have also included other complementary chemical, biophysical, and computational chemistry methods. This tutorial review describes the background to the technique of CD spectroscopy and good practice methods for high quality data collection. It specifically focuses on both established and new methods and tools available for experimental design and interpretation, data processing, visualisation, analysis, validation, archiving, and accession, including tools developed to enhance the complementarity of this method with other structural and chemical biology studies.