Electronic Circular Dichroism of [16]Helicene With Simplified TD‐DFT: Beyond the Single Structure Approach

The electronic circular dichroism (ECD) spectrum of the recently synthesized [16]helicene and a derivative comprising two triisopropylsilyloxy protection groups was computed by means of the very efficient simplified time‐dependent density functional theory (sTD‐DFT) approach. Different from many previous ECD studies of helicenes, nonequilibrium structure effects were accounted for by computing ECD spectra on "snapshots" obtained from a molecular dynamics (MD) simulation including solvent molecules. The trajectories are based on a molecule specific classical potential as obtained from the recently developed quantum chemically derived force field (QMDFF) scheme. The reduced computational cost in the MD simulation due to the use of the QMDFF (compared to ab‐initio MD) as well as the sTD‐DFT approach make realistic spectral simulations feasible for these compounds that comprise more than 100 atoms. While the ECD spectra of [16]helicene and its derivative computed vertically on the respective gas phase, equilibrium geometries show noticeable differences, these are “washed” out when nonequilibrium structures are taken into account. The computed spectra with two recommended density functionals (ωB97X and BHLYP) and extended basis sets compare very well with the experimental one. In addition we provide an estimate for the missing absolute intensities of the latter. The approach presented here could also be used in future studies to capture nonequilibrium effects, but also to systematically average ECD spectra over different conformations in more flexible molecules. Chirality 28:365–369, 2016. © 2016 Wiley Periodicals, Inc.     

Cationic oligopeptides with the repeating sequence L‐lysyl‐L‐alanyl‐L‐alanine: conformational and thermal stability study using optical spectroscopic methods

The infrared (IR), vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectra of short cationic sequential peptides (L ‐Lys‐L ‐Ala‐L ‐Ala)_n (n = 1, 2, and 3) were measured over a range of temperatures (20–90 °C) in aqueous solution at near‐neutral pH values in order to investigate their solution conformations and thermally induced conformational changes. VCD spectra of all three oligopeptides measured in the amide I′ region indicate the presence of extended helical polyproline II (PPII)‐like conformation at room temperature. UV‐ECD spectra confirmed this conclusion. Thus, the oligopeptides adopt a PPII‐like conformation, independent of the length of the peptide chain. However, the optimized dihedral angles ? and ψ are within the range ?82 to ?107° and 143–154°, respectively, and differ from the canonical PPII values. At elevated temperatures, the observed intensity and bandshape variations in the VCD and ECD spectra show that the PPII‐like conformation of the Lys‐Ala‐Ala sequence is still preferred, being in equilibrium with an unordered conformer at near‐neutral pH values within the range of temperatures from 20 to 90 °C. This finding was obtained from analysis of the temperature‐dependent spectra using the singular value decomposition method. The study presents KAA‐containing oligopeptides as conformationally stable models of biologically important cationic peptides and proteins. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.     

VCD studies on cyclic peptides assembled from L‐α‐amino acids and a trans‐2‐aminocyclopentane‐ or trans‐2‐aminocyclohexane carboxylic acid

The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans‐2‐aminocyclohexane carboxylic acid (Achc) or trans‐2‐aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three‐dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6‐31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR‐based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides. Copyright © 2010 European Peptide Society and John Wiley & Sons, Ltd.     

Absolute configuration determination and conformational analysis of (−)‐(3S,6S)‐3α,6β‐diacetoxytropane using vibrational circular dichroism and DFT techniques

The absolute configuration of semisynthetic (?)‐3α,6β‐acetoxytropane 1 , prepared from (?)‐6β‐hydroxyhyoscyamine 2 , has been determined using vibrational circular dichroism (VCD) spectroscopy. The vibrational spectra (IR and VCD) were calculated using DFT at the B3LYP/DGDZVP level of theory for the eight more stable conformers which account for 99.97% of the total relative abundance in the first 10 kcal/mol range. The calculated VCD spectra of all considered conformations showed two distinctive spectral ranges, one between 1300 and 1200 cm^?1, and the other one in the 1150–950 cm^?1 region. When compared with the experimental VCD spectrum, the first spectral region confirmed the calculated conformational preferences, whereas the second region showed little change with conformation, thus allowing the determination of the absolute configuration of 1 as (3S,6S)‐3α,6β‐diacetoxytropane. Also, the bands in the second region showed similarities between 1 and 2 in both the experimental and calculated VCD spectra, suggesting that these bands are mainly related to the absolute configuration of the rigid tropane ring system, since they show conformational independency, no variations with the nature of the substituent, and are composed by closely related vibrational modes. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Solvent‐dependent inversion of circular dichroism signal in naproxen: An unusual effect!

The electronic circular dichroism (ECD) spectra of naproxen enantiomers were studied as a function of solvents using experimental (circular dichroism) and theoretical (time‐dependent density functional theory) approaches. The (R)‐ and (S)‐naproxen enantiomers presented an unusual inversion in their ECD signals in the presence of ethanol and water when compared with polar aprotic solvents such as acetonitrile. From a practical point of view, these findings deserve great attention because these solvents are widely used for high‐performance liquid chromatography analysis in quality control of chiral pharmaceutical drugs. This is particularly relevant to naproxen because the (S)‐naproxen has anti‐inflammatory properties, whereas (R)‐naproxen is hepatotoxic. A time‐dependent density functional theory computer simulation was conducted to investigate the signal inversion using the solvation model based on density, a reparameterization of polarized continuum model. Electronic circular dichroism signals of conformers were calculated by computer simulation and their contribution to the combined spectra obtained according to Boltzmann weighting. It was found that the experimentally observed ECD signal inversion can be associated with the minor or major contribution of different conformers of naproxen.     

The effect of β‐methylation on the conformation of α, β‐dehydrophenylalanine: a DFT study

Dehydroamino acids are non‐coded amino acids that offer unique conformational properties. Dehydrophenylalanine (ΔPhe) is most commonly used to modify bioactive peptides to constrain the topography of the phenyl ring in the side chain, which commonly serves as a pharmacophore. The Ramachandran maps (in the gas phase and in CHCl₃ mimicking environments) of ΔPhe analogues with methyl groups at the β position of the side chain as well as at the C‐terminal amide were calculated using the B3LYP/6‐31 + G** method. Unexpectedly, β‐methylation alone results in an increase of conformational freedom of the affected ΔPhe residue. However, further modification by introducing an additional methyl group at C‐terminal methyl amide results in a steric crowding that fixes the torsion angle ψ of all conformers to the value 123°, regardless of the Z or E position of the phenyl ring. The number of conformers is reduced and the accessible conformational space of the residues is very limited. In particular, (Z)‐Δ(βMe)Phe with the tertiary C‐terminal amide can be classified as the amino acid derivative that has a single conformational state as it seems to adopt only the β conformation. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.     

A comparison of four different conformations adopted by human telomeric G‐quadruplex using computer simulations

The telomeric G‐quadruplexes for their unique structural features are considered as potential anticancer drug targets. These, however, exhibit structural polymorphism as different topology types for the intra‐molecular G‐quadruplexes from human telomeric G‐rich sequences have been reported based on NMR spectroscopy and X‐ray crystallography. These techniques provide detailed atomic‐level information about the molecule but relative conformational stability of the different topologies remains unsolved. Therefore, to understand the conformational preference, we have carried out quantum chemical calculations on G‐quartets; used all‐atom molecular dynamics (MD) simulations and steered molecular dynamics (SMD) simulations to characterize the four human telomeric G‐quadruplex topologies based on its G‐tetrad core‐types, viz., parallel, anti‐parallel, mixed‐(3 + 1)‐form1 and mixed‐(3 + 1)‐form2. We have also studied a non‐telomeric sequence along with these telomeric forms giving a comparison between the two G‐rich forms. The structural properties such as base pairing, stacking geometry and backbone conformations have been analyzed. The quantum calculations indicate that presence of a sodium ion inside the G‐tetrad plane or two potassium ions on both sides of the plane give it an overall planarity which is much needed for good stacking to form a helix. MD simulations indicate that capping of the G‐tetrad core by the TTA loops keep the terminal guanine bases away from water. The SMD simulations along with equilibrium MD studies indicate that the parallel and non‐telomeric forms are comparatively less stable. We could come to the conclusion that the anti‐parallel form and also the mixed‐(3 + 1)‐form1 topology are most likely to represent the major conformation., 2016. © 2015 Wiley Periodicals, Inc. Biopolymers 105: 83–99, 2016     

VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Synthesis,Structural Characterization,and Chiroptical Studies of Bidentate Salen‐Type Lanthanide (III) Complexes

The salen‐type ligand prepared with (R,R) diphenylethan‐1,2‐diamine and salicylaldehyde provides stable and inert complexes KLnL₂ upon simple reaction with lanthanide halides or pseudohalides LnX₃ (Ln = Tb³⁺‐Lu³⁺; X = Cl^? or TfO^?) of its potassium salt. All the complexes were completely characterized through nuclear magnetic resonance (NMR), electronic circular dichroism (ECD) in the UV and some (Er³⁺, Tm³⁺, Yb³⁺) also with Near‐IR ECD (NIR‐ECD) and luminescence (Tb³⁺, Tm³⁺). Careful analysis of the NMR shifts demonstrated that the complexes are isostructural in solution and afforded an accurate geometry. This was further confirmed by means of Density Functional Theory (DFT) optimization of the Lu³⁺ complex, and by comparing the ligand‐centered experimental and time‐dependent TD‐DFT computed UV‐ECD spectra. As final validation, we used the NIR‐ECD spectrum of the Yb³⁺ derivative calculated by means of Richardson's equations. The excellent match between calculated and experimental ECD spectra confirm the quality of the NMR structure.  Chirality 27:857–863, 2015. © 2015 Wiley Periodicals, Inc.     

Unusual CD couplet pattern observed for the pi*<--n transition of enantiopure (Z)-8-methoxy-4-cyclooctenone: an experimental and theoretical study by electronic and vibrational circular dichroism spectroscopy and density functional theory calculation

Ultraviolet absorption (UV) and electronic circular dichroism (ECD) spectra of enantiopure (Z)-8-methoxy-4-cyclooctenone (MCO) were measured in hexane to give a normal single UV absorption band at 298 nm, which is assigned to the carbonyl's pi*<--n transition. Unexpectedly, the ECD spectrum exhibited an apparent couplet pattern with vibrational fine structures. Obviously, the conventional CD exciton coupling mechanism cannot be applied to this bisignate CD signal observed for single-chromophoric MCO. Variable temperature-ECD and vibrational circular dichroism (VCD) spectral measurements, simultaneous UV and ECD spectral band resolution, and density functional theory (DFT) calculations of energy and structure revealed that this apparent CD couplet originates from a rather complicated spectral overlap of more than three conformers of MCO, two of which exhibit mirror-imaged ECD spectra at appreciably deviated wavelengths. In the simultaneous band-resolution analysis, the observed UV and ECD spectra were best fitted to four overlapping bands. Two major conformers were identified by comparing the experimental IR and VCD spectra with the simulated ones, and the other two by comparing the observed UV and ECD spectra with the theoretical ones obtained by time-dependent DFT calculations. It was shown that the combined use of experimental ECD and VCD spectra and theoretical DFT calculations can give a reasonable interpretation for the Cotton effects of the conformationally flexible molecule MCO.     

(R)‐Metacycloprodigiosin‐HCl: Chiroptical properties and structure

(R)‐Metacycloprodigiosin can exist in three different tautomeric forms, each with hydrogens at C9′ and C12 in syn or anti orientation. With the addition of HCl, this structural diversity reduces to syn‐(R)‐metacycloprodigiosin‐HCl ( 1a ) and anti‐(R)‐metacycloprodigiosin‐HCl ( 1b ), each with multiple conformers. Energetics and chiroptical properties, namely, electronic circular dichroism (ECD) and specific optical rotation (SOR), of (R)‐metacycloprodigiosin‐HCl have been investigated at B3LYP/6‐311++G(2d,2p) level. The experimental ECD spectra of (R)‐metacycloprodigiosin‐HCl have also been measured. Calculations indicated that the lowest energy conformer of 1b is approximately 2.7 kcal/mol lower in energy than that of 1a , and the energy barrier for anti to syn conversion is approximately 13 kcal/mol. The population weighted calculated SORs of 1a and 1b are, respectively, positive and negative. The respective calculated ECD spectra of these pseudoenantiomers show an almost mirror image relationship between them. The experimental SOR and ECD compare well with those predicted for 1b . Thus, 1b is expected to be predominant, a situation confirmed also by nuclear Overhauser effect (NOE) data, with a similar conclusion reached for prodigiosin R1.     

CD spectrum and conformational distribution of cyclotuftsin in solution

CD spectra for low-energy conformations of the tuftsin cycloanalogue, , were calculated. A theoretical spectrum obtained as the weighted average of calculated spectra for individual peptide backbone conformers is qualitatively consistent with an experimental CD spectrum in aqueous solution. The conformational distribution allows one to achieve agreement between calculated and experimental values of structural parameters of the cyclotuftsin molecule investigated by NMR spectroscopy.

CD spectrum calculation Theoretical conformational analysis Tuftsin cycloanalog Peptide conformation     

High‐resolution crystal structures reveal a mixture of conformers of the Gly61‐Asp62 peptide bond in an oxidized flavodoxin from Bacillus cereus

Flavodoxins (Flds) are small proteins that shuttle electrons in a range of reactions in microorganisms. Flds contain a redox‐active cofactor, a flavin mononucleotide (FMN), and it is well established that when Flds are reduced by one electron, a peptide bond close to the FMN isoalloxazine ring flips to form a new hydrogen bond with the FMN N5H, stabilizing the one‐electron reduced state. Here, we present high‐resolution crystal structures of Flavodoxin 1 from Bacillus cereus in both the oxidized (ox) and one‐electron reduced (semiquinone, sq) state. We observe a mixture of conformers in the oxidized state; a 50:50 distribution between the established oxidized conformation where the peptide bond is pointing away from the flavin, and a conformation where the peptide bond is pointing toward the flavin, approximating the conformation in the semiquinone state. We use single‐crystal spectroscopy to demonstrate that the mixture of conformers is not caused by radiation damage to the crystal. This is the first time that such a mixture of conformers is reported in a wild‐type Fld. We therefore carried out a survey of published Fld structures, which show that several proteins have a pronounced conformational flexibility of this peptide bond. The degree of flexibility seems to be modulated by the presence, or absence, of stabilizing interactions between the peptide bond carbonyl and its surrounding amino acids. We hypothesize that the degree of conformational flexibility will affect the Fld ox/sq redox potential.     

Dual spatial folds and different local structures of the HIV-1 immunogenic crown in various virus isolates

Local and global structural properties of the HIV-1 principal neutralizing epitope were studied in terms of NMR spectroscopy data reported in literature for the HIV-Haiti and HIV-RF isolates. To this effect, the NMR-based method comprising a probabilistic model of protein conformation in conjunction with the molecular mechanics and quantum chemical computations was used for determining the ensembles of conformers matching the NMR requirements and energy criteria. As a matter of record, the high resolution 3D structure models were constructed for the HIV-Haiti and HIV-RF immunogenic crowns, and their geometric parameters were collated with the ones of conformers derived previously for describing the conformational features of immunogenic tip of gp120 from Thailand and MN HIV-1 strains. The HIV-1 neutralization site was demonstrated to constitute in water solution highly flexible system sensitive to its environment. This inference is completely valid for the geometric space of dihedral angles where statistically significant differences in local structures of simulated conformers have been found for all virus isolates of interest. In spite of this fact, the stretch analyzed was shown to manifest a certain conservatism in the space of atomic coordinates, building up in four HIV-1 isolates two spatial folds similar to those observed in crystal for the V3 loop peptides bound to different neutralizing Fabs. The results are discussed in the light of literature data on HIV-1 neutralizing epitope structure.     

From Cats and Blackcurrants: Structure and Dynamics of the Sulfur‐Containing Cassis Odorant Cat Ketone

Sulfur‐containing odorants and flavors play an important role in flavor and food industry, especially when meaty, garlic, onion, and vegetable scents are needed. Still, many S‐containing flavors also possess fruity scents and may be used in compositions of perfumes that require a fresh and fruity odor perception. They are naturally abundant in various fruits, essential oils, and food. Most of these compounds possess strong scents, and their scent composition is highly dependent on the concentration applied. At higher concentrations, they usually feature repellent off‐odors, while their sweet and fruity nature is only experienced at very low concentrations. This represents a challenge for their application in perfumery, as well as in food industry. From a molecular point of view, the endless structural and scent variety of these compounds makes them fascinating, especially as their O‐analogs are usually free of any malodors. Here, we report on the investigation of the gas‐phase structure and dynamics of the S‐containing blackcurrant odorant cat ketone (4‐methyl‐4‐sulfanylpentan‐2‐one). The work was performed by combining quantum‐chemical calculations and molecular‐beam Fourier‐transform microwave spectroscopy as complementary tools. Using this technique, we are able to determine the structures of sizeable molecules where energy differences are small and conformational distinction is not always possible by quantum‐chemical calculations alone. The presented results can be used for further structure? activity correlation studies, as well as for benchmarks to improve theoretical models, especially, as there is still significant interest in characterizing the various conformers of organic molecules in terms of relative energies, structures, and dipole moments.     

HPLC‐ECD and TDDFT‐ECD study of hexahydropyrrolo[1,2‐a]quinoline derivatives

Synthesis of racemic hexahydropyrrolo[1,2‐a]quinoline derivatives ( 1 ‐ 8 ) was performed by utilizing the Knoevenagel‐[1,5]‐hydride shift‐cyclization domino reaction. Separation of the enantiomers of the chiral products ( 1 ‐ 8 ) was carried out by chiral high‐performance liquid chromatography, and online high‐performance liquid chromatography‐electronic circular dichroism (ECD) spectra were recorded to elucidate the absolute configuration by comparing the experimental and time‐dependent density functional theory‐ECD spectra obtained at various theoretical levels. For 1 of the products, the time‐dependent density functional theory‐ECD calculations allowed determining both the relative and the absolute configuration by distinguishing the 4 stereoisomers. One of the compounds with spiro 1,3‐cyclohexanedione moiety ( 7 ) possessed moderate acetylcholinesterase inhibitory activity, while 3 showed neuroprotective activity in oxygen‐glucose deprivation‐induced neurotoxicity in human neuroblastoma SH‐SY5Y cells.     

Identification of putative unfolding intermediates of the mutant His‐107‐tyr of human carbonic anhydrase II in a multidimensional property space

In this article, we develop an extensive search procedure of the multi‐dimensional folding energy landscape of a protein. Our aim is to identify different classes of structures that have different aggregation propensities and catalytic activity. Following earlier studies by Daggett et al. [Jong, D. D.; Riley, R.: Alonso, D.O.: Dagett, V. J. Mol. Biol. 2002, 319, 229], a series of high temperature all‐atom classical molecular simulation studies has been carried out to derive a multi‐dimensional property space. Dynamical changes in these properties are then monitored by projecting them along a one‐dimensional reaction coordinate, d_mean. We have focused on the application of this method to partition a wide array of conformations of wild type human carbonic anhydrase II (HCA II) and its unstable mutant His‐107‐Tyr along d_mean by sampling a 35‐dimensional property space. The resultant partitioning not only reveals the distribution of conformations corresponding to stable structures of HCA II and its mutant, but also allows the monitoring of several partially unfolded and less stable conformations of the mutant. We have investigated the population of these conformations at different stages of unfolding and collected separate sets of structures that are widely separated in the property space. The dynamical diversity of these sets are examined in terms of the loading of their respective first principal component. The partially unfolded structures thus collected are qualitatively mapped on to the experimentally postulated light molten globule (MGL) and molten globule (MG) intermediates with distinct aggregation propensities and catalytic activities. Proteins 2016; 84:726–743. © 2016 Wiley Periodicals, Inc.     

Assessment of configurational and conformational properties of naringenin by vibrational circular dichroism

The electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectra of both enantiomers of naringenin (4',5,7-trihydroxyflavanone) in acetonitrile solution have been measured. The enantiomers were obtained by chiral HPLC separation of the racemic sample. DFT calculations have been performed for relevant conformers and subsequent evaluations of VCD spectra are compared with VCD experiments: safe assignment of the absolute configuration is provided, based in particular on the VCD data. The relevance of the rotational conformers of the hydroxyl groups and of the mobility of phenol moiety is studied: based on this, we provide a first interpretation of the observed intense and broad couplet at 1325/1350 cm(-1). Four conformers contribute to this pattern with different sign and amplitude as shown by DFT calculations. Time dependent DFT calculations have been performed and compared with ECD experimental data, under the same assumption of conformational properties and mobilities investigated by VCD.