Conformational Equilibrium In Solution Research Articles

Solvent-Dependent Conformational Switching of N-Methyl-N,N'-diarylsquaramide.

N,N'-Diarylsquaramide and N,N'-dialkylsquaramide are conformationally stable linkers with extended (trans, trans) and folded (cis, cis) structures, respectively, independently of external conditions. Here, we show that N-monomethylated N,N'-diarylsquaramides generally take a (trans, cis) structure in the crystal but show a solvent-dependent conformational equilibrium in solution. In particular, the stable conformer of N-methyl-N,N'-bis(1-naphthyl)squaramide (1f) changes depending upon the solvent. Thus, aromatic N-monomethylated squaramides could find application as components of environment-responsive molecular switches.

E-Volve: understanding the impact of mutations in SARS-CoV-2 variants spike protein on antibodies and ACE2 affinity through patterns of chemical interactions at protein interfaces.

BackgroundThe SARS-CoV-2 pandemic reverberated, posing health and social hygiene obstacles throughout the globe. Mutant lineages of the virus have concerned scientists because of convergent amino acid alterations, mainly on the viral spike protein. Studies have shown that mutants have diminished activity of neutralizing antibodies and enhanced affinity with its human cell receptor, the ACE2 protein.MethodsHence, for real-time measuring of the impacts caused by variant strains in such complexes, we implemented E-Volve, a tool designed to model a structure with a list of mutations requested by users and return analyses of the variant protein. As a proof of concept, we scrutinized the spike-antibody and spike-ACE2 complexes formed in the variants of concern, B.1.1.7 (Alpha), B.1.351 (Beta), and P.1 (Gamma), by using contact maps depicting the interactions made amid them, along with heat maps to quantify these major interactions.ResultsThe results found in this study depict the highly frequent interface changes made by the entire set of mutations, mainly conducted by N501Y and E484K. In the spike-Antibody complex, we have noticed alterations concerning electrostatic surface complementarity, breaching essential sites in the P17 and BD-368-2 antibodies. Alongside, the spike-ACE2 complex has presented new hydrophobic bonds.DiscussionMolecular dynamics simulations followed by Poisson-Boltzmann calculations corroborate the higher complementarity to the receptor and lower to the antibodies for the K417T/E484K/N501Y (Gamma) mutant compared to the wild-type strain, as pointed by E-Volve, as well as an intensification of this effect by changes at the protein conformational equilibrium in solution. A local disorder of the loop α1′/β1′, as well its possible effects on the affinity to the BD-368-2 antibody were also incorporated to the final conclusions after this analysis. Moreover, E-Volve can depict the main alterations in important biological structures, as shown in the SARS-CoV-2 complexes, marking a major step in the real-time tracking of the virus mutant lineages. E-Volve is available at http://bioinfo.dcc.ufmg.br/evolve.

Self-Assembly of an Amphiphilic Bile Acid Dimer: A Combined Experimental and Theoretical Study of Its Medium-Responsive Fluorescence.

This work describes the synthesis and aggregation behavior of a dimeric bile acid derivative in which two steroid cores are bridged by a p-di(phenylethynyl)phenylene fluorophore. The studied compound contains three key characteristics: (a) restricted conformational equilibrium in solution, (b) efficient fluorescence conferred by the bridge, and (c) medium responsiveness encoded in the steroid fragments. The incorporation of the three components afforded a compound that generates nano- and micrometric spherical particles with aggregation-responsive fluorescence emission. The observed self-assembly process of the featured molecule was induced by the gradual addition of water to the tetrahydrofuran (THF) solution. This aggregation led to significant changes in fluorescence that went from two bands at λem values of 370 and 390 nm in pure THF to a new spectrum with two maxima at λem values of 395 and 418 nm at high water contents, without a decrease in emission. The observed changes can be ascribed to weakly coupled aggregation, a hypothesis supported by multiscale molecular modeling, which sheds light on the mechanism of the self-assembly of this unconventional amphiphile.

MA'AT Analysis of Aldofuranosyl Rings: Unbiased Modeling of Conformational Equilibria and Dynamics in Solution.

MA'AT analysis has been applied to methyl β-d-ribofuranoside (3) and methyl 2-deoxy-β-d-erythro-pentofuranoside (4) to demonstrate the ability of this new experimental method to determine multi-state conformational equilibria in solution. Density functional theory (DFT) was used to obtain parameterized equations for >20 NMR spin-coupling constants sensitive to furanose ring conformation in 3 and 4, and these equations were used in conjunction with experimental spin-couplings to produce unbiased MA'AT models of ring pseudorotation. These models describe two-state north-south conformational exchange consistent with results obtained from traditional treatments of more limited sets of NMR spin-couplings (e.g., PSEUROT). While PSEUROT, MA'AT, and aqueous molecular dynamics models yielded similar two-state models, MA'AT analysis gives more reliable results since significantly more experimental observables are employed compared to PSEUROT, and no assumptions are needed to render the fitting tractable. MA'AT models indicate a roughly equal distribution of north and south ring conformers of 4 in aqueous (2H2O) solution compared to ∼80% north forms for 3. Librational motion about the mean pseudorotation phase angles P of the preferred north and south conformers of 3 in solution is more constrained than that for 4. The greater rigidity of the β-ribo ring may be caused by synergistic stereoelectronic effects and/or noncovalent (e.g., hydrogen-bonding) interactions in solution that preferentially stabilize north forms of 3. MA'AT analysis of oligonucleotides and other furanose ring-containing biomolecules promises to improve current experimental models of sugar ring behavior in solution and help reveal context effects on ring conformation in more complex biologically important systems.

Conformation equilibrium of 3-(hydroxymethyl)piperidine in solvents with different polarity

Quantum-chemical calculations of the 3-(hydroxymethyl)piperidine molecule conformers were performed at the B3LYP/6-31+G** level of theory, and four most stable conformations with different relative orientation of CH2OH and N–H groups were determined. The optimized structures, vibration frequencies, and band intensities in the spectra of the conformers were obtained. The conformational equilibria of the most stable rotational isomers in solvents of different polarity was studied within the polarizable continuum model. According to the results of calculations, the conformational equilibrium in solution is substantially changed on varying the solvent polarity. This conclusion was confirmed by comparison with IR absorption spectra of 3-(hydroxymethyl)piperidine solutions in carbon tetrachloride in the region of ОН-stretchings.

Analyzing slowly exchanging protein conformations by ion mobility mass spectrometry: study of the dynamic equilibrium of prolyl oligopeptidase.

Ion mobility mass spectrometry (IMMS) is a biophysical technique that allows the separation of isobaric species on the basis of their size and shape. The high separation capacity, sensitivity and relatively fast time scale measurements confer IMMS great potential for the study of proteins in slow (µs-ms) conformational equilibrium in solution. However, the use of this technique for examining dynamic proteins is still not generalized. One of the major limitations is the instability of protein ions in the gas phase, which raises the question as to what extent the structures detected reflect those in solution. Here, we addressed this issue by analyzing the conformational landscape of prolyl oligopeptidase (POP) - a model of a large dynamic enzyme in the µs-ms range - by native IMMS and compared the results obtained in the gas phase with those obtained in solution. In order to interpret the experimental results, we used theoretical simulations. In addition, the stability of POP gaseous ions was explored by charge reduction and collision-induced unfolding experiments. Our experiments disclosed two species of POP in the gas phase, which correlated well with the open and closed conformations in equilibrium in solution; moreover, a gas-phase collapsed form of POP was also detected. Therefore, our findings not only support the potential of IMMS for the study of multiple co-existing conformations of large proteins in slow dynamic equilibrium in solution but also stress the need for careful data analysis to avoid artifacts. Copyright © 2016 John Wiley & Sons, Ltd.

Isolation and structural characterization of new piperidine alkaloids from Prosopis affinis

The isolation of three new N-methylated piperidine-3-ol alkaloids from the bark of Prosopis affinis Spreng. (Ñandubay) is described. Together with MS and IR data, results from 1D and 2D NMR experiments allowed for the identification of N‑methyl-2-isocassine, N‑methyl-6-isocassine, and N‑methyl-6-isocarnavaline. Inspection of 1D-NOESY spectra and coupling constant data revealed that the heterocyclic moiety of the alkaloids is in fast conformational equilibrium in solution, and this behavior had to be taken into account in order to determine the relative configuration of the chiral centers of the piperidine rings.

Complexation of solvents and conformational equilibria in solutions of the simplest calix[4]arenes

Structure optimization and calculation of electronic adsorption spectra of 25,26,27,28-tetrahydroxycalix[4]arene and 25,27-dimethoxy-26,28-dihydroxycalix[4]arene conformers have been performed by density-functional theory using hybrid B3LYP functional in cc-p VTZ and cc-p VDZ basis sets in Gaussian 09 package. Analysis of experimental UV–Vis spectra of solutions of 25,26,27,28-tetrahydroxycalix[4]arene, 4-tert-butylcalix[4]arene and 25,27-dimethoxy-26,28-dihydroxycalix[4]arene in various solvents has been carried out. It was shown that the ratio of absorption maxima at characteristic wavelengths at ca. 274 and 283nm may be used to assess the extent of calix[4]arene/solvent interactions. The conclusion is drawn that spectral characteristics of calix[4]arenes are strongly affected by acid–base interactions.

Chiral and Achiral Charge‐Transfer Chromophores with a Dendralene‐Type Backbone by Electronically Controlled Cycloaddition/Cycloreversion Cascades

AbstractChiral and achiral push‐pull chromophores have been prepared by cascades of sequential [2+2] cycloadditions of tetracyanoethene (TCNE) and tetrathiafulvalene (TTF) to different oligoynes. Thermal [2+2] cycloaddition of TCNE to donor‐substituted alkynes, followed by electrocyclic ring‐opening of the initially formed cyclobutenes, affords donor‐substituted 1,1,4,4‐tetracyanobuta‐1,3‐dienes (TCBDs). Similarly, TTF reacts with electron‐deficient C≡C bonds to give the corresponding buta‐1,3‐diene derivatives, 1,2‐bis(1,3‐dithiol‐2‐ylidene)ethanes. Thus, achiral [AB]‐type oligomers were synthesized from N,N‐dialkylanilino (DAA)‐substituted tetraynes and hexaynes and chiral [AB]‐type oligomers from alkyne‐substituted 1,1′‐binaphthalenes. The [AB]‐type oligomers exhibit complex conformational equilibria in solution, as revealed by 1H and 13C NMR spectroscopy. Therefore, the circular dichroism (CD) spectra of the chiral [AB]‐type oligomers were measured to investigate whether a preferred conformation of the dendralene‐type backbone is induced by the optically active 1,1′‐binaphthalene moiety. Electrochemical studies by cyclic voltammetry (CV) and rotating‐disk voltammetry (RDV) showed large cathodic shifts of the first oxidation potentials for some of the chiral and achiral [AB]‐type oligomers due to sterically enforced π‐deconjugation of the acceptor and donor moieties. The new multivalent systems feature intense, bathochromically shifted intramolecular charge‐transfer (CT) bands in the UV/Vis spectra. Extended, donor‐substituted TCBDs, which are obtained by mono‐addition of TCNE to the hexaynes, exhibit low optical and electrochemical HOMO–LUMO gaps. In addition, a large third‐order optical nonlinearity was measured for one of these TCBDs by degenerate four‐wave mixing (DFWM).

Interpretation of Raman and Raman Optical Activity Spectra of a Flexible Sugar Derivative, the Gluconic Acid Anion

Raman scattering and its polarized extension, Raman optical activity (ROA), are commonly used for monitoring of molecular conformational equilibria in solutions. This is complicated for saccharides due to extensive motions of the hydroxyl groups and other molecular parts. Standard interpretation procedures involving ab initio spectral simulations for a limited set of conformers are not adequate. In this study, a more general approach is proposed for the gluconic acid anion taken as a model compound, where quantum simulations of the spectra are directly coupled with molecular dynamics (MD) techniques. Such a multiscale approach reveals how the structural information is encoded in the broadened spectral lines. The spectra were simulated for solvent-solute clusters generated by MD. Conformational averaging was enabled by a limited library of conformers for which the spectral parameters could be calculated ab initio and moved on the MD geometries by Cartesian coordinate tensor transfer techniques. The B3LYP/CPCM/6-31+G** approximation was used as a default for computation of the source force fields and polarizability derivatives. The spectra thus obtained relatively faithfully reproduced most of the experimental features. The Amber and polarizable Amoeba MD force fields produced similar results; application of the latter, however, was limited by the long time necessary to achieve a converged conformational equilibrium. Both MD simulation and spectral averaging suggest that the hydroxyl groups as well as the backbone C-C bonds rotate relatively freely, with some restrictions in the vicinity of the carboxyl group. In spite of the averaging, spectral response of characteristic vibrational normal mode families, such as CH and OH bending, can clearly be identified in the spectra. The simulations thus confirm the experimental fact that flexible saccharides exhibit significant vibrational activity that reveals precious information about molecular structure and dynamics encoded in the Raman and ROA spectral shapes.

Role of the gauche effect and local 1,3-dipole–dipole interactions in stabilizing an unusual conformation of tartarodinitriles

This paper reports the synthesis, X-ray and NMR investigations of chiral and meso dinitriles of tartaric acid (tartarodinitriles) and their O,O'-diacetyl and O,O'-dibenzoyl derivatives. While in chiral tartaric acid its esters and NH amides the four-atom carbon chain is overwhelmingly trans, it is gauche in chiral tartarodinitriles. Conversely, meso-tartaric acid, its esters and amides display a tendency for the gauche conformation, but meso-tartarodinitriles usually have the trans conformation. The NMR studies of tartarodinitriles reveal the presence of a conformational equilibrium in solution with a preference for those conformers found in crystals. The gauche conformation of meso-tartarodinitriles seems to be stabilized by local dipolar interactions, intramolecular C-H...O hydrogen bonds and by a tendency for maximization of the gauche effect, the latter effect also operating in chiral tartarodinitriles. Stabilization of the trans conformers of tartarodinitriles in the crystals seems to originate from specific intermolecular interactions.

Excited state behaviour of some thio-analogues of 1,3-distyrylbenzene

The excited state properties of 1, n-distyrylbenzene ( n = 2, 3 or 4) and hetero-analogues have being investigated in the authors’ laboratory by fluorimetry, nanosecond and femtosecond laser flash photolysis, and conventional photochemical techniques as well as by the help of theoretical calculations. The aim of the present article is to survey recent results of the study on the internal rotation around double bonds, i.e. cis– trans photoisomerization ( cis and trans are indicated in the text by Z and E, respectively) and single bonds (i.e. conformational equilibria) in some thio-analogues of E, E-1,3-distyrylbenzene where the central or side benzene rings were replaced by thiophene rings. Some peculiarities in the photobehaviour of these compounds will be thus evidenced. The main effect of the sulphur heteroatom in the side rings is a decrease in the radiative relaxation and an increase in the E, E → Z, E photoisomerization yield caused by decreased torsional barriers in S 1 and/or increased triplet yields, which opens the way to isomerization in the triplet manifold. On the other hand, when sulphur is in the central ring, the fluorescence decrease favours non-reactive and non-radiative deactivations. In the case of 2,5-distyrylthiophene with a central thiophene ring, the photobehaviour of the stereoisomers with one or both cis double bonds ( Z, E and Z, Z) showed diabatic/adiabatic formation of the E, E isomer in both lowest excited states of singlet and triplet multiplicities. In the case of Z, Z, the adiabatic process (directly from Z, Z * to E, E *) is characterized by a “one photon–two bonds” mechanism. The presence of conformational equilibria in solutions of distyrylbenzenes was found to play a role in their relaxation properties since different conformers can have different deactivation channels, specifically in the case of the 1,3 compound with side 3′-thienyl groups. The results obtained by selective irradiation, as a function of the excitation wavelength and temperature, and supported by theoretical calculations, evidenced uncommon rotamer interconversion during the short S 1 lifetime of this compound.

New fluorescent monomers and polymers displaying an intramolecular proton‐transfer mechanism in the electronically excited state (ESIPT). IV. Synthesis of acryloylamide and diallylamino benzazole dyes and its copolymerization with MMA

AbstractSix new fluorescent monomers were synthesized by reaction of 2‐(5′‐amino‐2′‐hydroxyphenyl)benzazole derivatives with acryloyl chloride and allyl bromide. UV–vis and steady‐state fluorescence in solution were used to characterize its photophysical behavior. The monomers are fluorescent in the blue, green, yellow, and red region, with a large Stokes shift between 92 and 226 nm. A dual fluorescence ascribed to a conformational equilibrium in solution in the ground state dependent on the solvent polarity could be observed in the fluorescence emission spectra of the monomers. The radical polymerization of the monomers with methyl(methacrylate) allowed the production of fluorescent polymers in the blue–green region, with good optical and thermal properties. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci, 2006

Unique Stereochemistry of 3‐Borabicyclo[3.3.1]nonane Derivatives.

The conformational equilibrium in solution was examined by NMR spectroscopy for a series of 7α-phenyl-3-borabicyclo[3.3.1]nonane derivatives containing various substituents at the boron atom. The structures of these derivatives were studied in the crystalline state (X-ray diffraction analysis) and by quantum-chemical calculations (B3Pw91/6-31G*). The B...Ph transannular interactions corresponding to charge transfer from the π system of the phenyl group to the vacant p-orbital of the B atom were demonstrated to be responsible for unique stability of the chair-chair conformation of these derivatives.

New fluorescent monomers and polymers displaying an intramolecular proton-transfer mechanism in the electronically excited state (ESIPT): Part II. Synthesis, spectroscopic characterization and solvatochromism of new benzazolylvinylene derivatives

Eight new highly fluorescent benzazolylvinylene monomers were synthesized by reaction of 2-(4′-amino-2′-hydroxyphenyl)benzazoles with two functionalized vinylene derivatives and acryloyl chloride. The monomers were characterized by means of infrared, 13C and 1H-NMR and elemental analysis. UV–vis and steady-state fluorescence in solution were also applied in order to characterize its photophysical behaviour. The benzoxazole and benzimidazole derivatives are fluorescent in the blue–purple region and the benzothiazole in the green region. The monomers presented a Stokes shift between 51 and 159 nm. A dual fluorescence ascribed to a conformational equilibrium in solution in the ground state dependent on the solvent polarity could be observed in the monomers. The radical polymerization of the monomers with methyl(methacrylate) allowed the production of eight new fluorescent polymers with good optical and thermal properties.

Unique stereochemistry of 3-borabicyclo[3.3.1]nonane derivatives

The conformational equilibrium in solution was examined by NMR spectroscopy for a series of 7α-phenyl-3-borabicyclo[3.3.1]nonane derivatives containing various substituents at the boron atom. The structures of these derivatives were studied in the crystalline state (X-ray diffraction analysis) and by quantum-chemical calculations (B3Pw91/6-31G*). The B...Ph transannular interactions corresponding to charge transfer from the π system of the phenyl group to the vacant p-orbital of the B atom were demonstrated to be responsible for unique stability of the chair-chair conformation of these derivatives.

NMR Spectroscopy in the Study of Carbohydrates : Characterizing the Structural Complexity

AbstractFor Abstract see ChemInform Abstract in Full Text.

Conformational Studies of Novel Antiretroviral Analogs of Zidovudine

Conformational properties of three novel zidovudine analogs, namely 3′-azido-3′-deoxy-5′-O-isonicotinoylthymidine (AZT-Iso, 2), (−)-trans-(5S,6S)-5-bromo-6, 5′-epoxy-5,6-dihydro-3′-azido-3′-deoxythymidine (3) and (+)-trans-(5R,6R)-5-bromo-6,5′-epoxy-5,6-dihydro-3′-azido-3′-deoxythymidine (4), have been investigated by AM1 calculations and NMR studies, and compared with those of the parent nucleoside (AZT, 1). Based on the results obtained the following correlation may be established, a) AZT and AZT-Iso exhibit a conformational behavior analog to other pyrimidinic nucleosides, displaying a dynamic equilibrium in solution where the two conformers (North and South) undergo a constant transformation. b) Compounds 3 and 4 show a different conformational profile. The estimate of the pseudorotation phase angle reveals the rigid structures of the latter compounds, which do not evidence conformational equilibrium in solution; theazide group being the only group free to rotate. c) Diastereoisomers 3 and 4 exhibit an extra conformational parameter compared with other pyrimidinic nucleosides: the chair or boat conformation in the third ring formed between the sugar and the base. In all cases, a reasonable correlation was obtained between theoretical and NMR spectroscopic data.

NMR spectroscopy in the study of carbohydrates: Characterizing the structural complexity

AbstractThe combination of structural diversity at several levels and limited chemical shift dispersion ensures that NMR spectra of carbohydrates are relatively difficult to interpret. This introduction to applications of NMR spectroscopy for the study of carbohydrates provides guidelines for interpretation of their 1‐ and 2‐D spectra against a background of their tautomeric, configurational, and conformational equilibria in solution and consideration of their biosynthetic diversity. The influence of structural features on chemical shifts and coupling constants is illustrated by the consequences for both homo‐ and heteronuclear 2‐D NMR spectra. Some applications of NMR spectroscopy for studies of carbohydrate metabolism are briefly considered. © 2003 Wiley Periodicals, Inc. Concepts Magn Reson 19A: 1–19, 2003.

Conformational equilibria in EE-2,6-di-[2-(furan-2-yl)vinyl]pyridine controlled by intramolecular hydrogen-type bonds

The conformational equilibria in solutions of the title compound were studied by a combined kinetic and statistical fluorimetric analysis in 9:1 methylcyclohexane/3-methylpentane at 293 K. The temperature and solvent effects on the equilibrium were also investigated. Two rotamers were evidenced: one short living, absorbing at shorter wavelengths, and a longer-lived one, more stable and with a bathochromically shifted absorption spectrum. The stabilising effect of intramolecular hydrogen bonds on the latter is discussed. The analysis allowed the spectral and radiative relaxation parameters of the two rotamers to be obtained.