Intensity‐Carrying Modes in Raman and Raman Optical Activity Spectroscopy

We describe a quantum‐chemical approach for the determination of modes with maximum Raman and Raman optical activity (ROA) intensity by maximizing the intensities with respect to the Raman and Raman optical activity intensity, respectively, which is shown to lead to eigenvalue equations. The intensity‐carrying modes are in general hypothetical modes and do not directly correspond to a certain normal mode in the spectrum. However, they provide information about those molecular distortions leading to intense bands in the spectrum. Modes with maximum Raman intensity are presented for propane‐1,3‐dione, propane‐1,3‐dionate, and Λ‐tris(propane‐1,3‐dionato)cobalt(III). Moreover, the mode with highest ROA intensity is examined for this chiral cobalt complex and also for the (chiral) amino acid L ‐tryptophan. The Raman and ROA high‐intensity modes are an optimal starting guess for intensity‐tracking calculations, in which selectively normal modes with high Raman or ROA intensity are converged. We present the first Raman and ROA intensity‐tracking calculations. These reveal a high potential for large molecules, for which the selective calculation of normal modes with high intensity is desirable in view of the large computational effort required for the calculation of Raman and ROA polarizability property tensors.     

Three Types of Induced Tryptophan Optical Activity Compared in Model Dipeptides: Theory and Experiment

The tryptophan (Trp) aromatic residue in chiral matrices often exhibits a large optical activity and thus provides valuable structural information. However, it can also obscure spectral contributions from other peptide parts. To better understand the induced chirality, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) spectra of Trp‐containing cyclic dipeptides c‐(Trp‐X) (where X=Gly, Ala, Trp, Leu, nLeu, and Pro) are analyzed on the basis of experimental spectra and density functional theory (DFT) computations. The results provide valuable insight into the molecular conformational and spectroscopic behavior of Trp. Whereas the ECD is dominated by Trp π–π* transitions, VCD is dominated by the amide modes, well separated from minor Trp contributions. The ROA signal is the most complex. However, an ROA marker band at 1554 cm^?1 indicates the local χ₂ angle value in this residue, in accordance with previous theoretical predictions. The spectra and computations also indicate that the peptide ring is nonplanar, with a shallow potential so that the nonplanarity is primarily induced by the side chains. Dispersion‐corrected DFT calculations provide better results than plain DFT, but comparison with experiment suggests that they overestimate the stability of the folded conformers. Molecular dynamics simulations and NMR results also confirm a limited accuracy of the dispersion‐DFT model in nonaqueous solvents. Combination of chiral spectroscopies with theoretical analysis thus significantly enhances the information that can be obtained from the induced chirality of the Trp aromatic residue.     

Preferred conformation of the glycosidic linkage of methyl-beta-mannose

The conformational preference of the glycosidic linkage of methyl-beta-mannose was studied in the gas phase and in aqueous solution by ab initio calculations, and by molecular dynamics (MD) and Car-Parrinello molecular dynamics (CPMD) simulations. MD simulations were performed with various water potential functions to study the impact of the chosen water potential on the predicted conformational preference of the glycosidic linkage of the carbohydrate in solution. This study shows that the trans (t) orientation of the glycosidic linkage of methyl-beta-mannose is preferred over its gauche clockwise (g+) orientation in solution. CPMD simulations clearly indicate that this preference is due to intermolecular hydrogen bonding with surrounding water molecules, whereas no such information could be demonstrated by MD simulations. This study demonstrates the importance of ab initio molecular dynamics simulations in studying the structural properties of carbohydrate-water interactions.     

Structures in solutions from joint experimental-computational analysis: applications to cyclic molecules and studies of noncovalent interactions

The potential of an approach combining nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) simulations, and quantum mechanical (QM) calculations for full structural characterizations in solution is assessed using cyclic organic compounds, namely, benzazocinone derivatives 1-3 with fused five- and eight-membered aliphatic rings, camphoric anhydride 4, and bullvalene 5. Various MD simulations were considered, using force field and semiempirical QM treatments, implicit and explicit solvation, and high-temperature MD calculations for selecting plausible molecular geometries for subsequent QM geometry optimizations using mainly B3LYP, M062X, and MP2 methods. The QM-predicted values of NMR parameters were compared to their experimental values for verification of the final structures derived from the MD/QM analysis. From these comparisons, initial estimates of quality thresholds (calculated as rms deviations) were 0.7-0.9 Hz for (3)J(HH) couplings, 0.07-0.11 ? for interproton distances, 0.05-0.08 ppm for (1)H chemical shifts, and 1.0-2.1 ppm for (13)C chemical shifts. The obtained results suggest that the accuracy of the MD analysis in predicting geometries and relative conformational energies is not critical and that the final geometry refinements of the structures selected from the MD simulations using QM methods are sufficient for correcting for the expected inaccuracy of the MD analysis. A unique example of C(sp(3))-H···N(sp(3)) intramolecular noncovalent interaction is also identified using the NMR/MD/QM and the natural bond orbital analyses. As the NMR/MD/QM approach relies on the final QM geometry optimization, comparisons of geometric characteristics predicted by different QM methods and those from X-ray and neutron diffraction measurements were undertaken using rigid and flexible cyclic systems. The joint analysis shows that intermolecular noncovalent interactions present in the solid state alter molecular geometries significantly compared to the geometries of isolated molecules from QM calculations.     

Diagnostic ions for the rapid analysis by nano-electrospray ionization quadrupole time-of-flight mass spectrometry of O-glycans from human mucins

Nano-electrospray ionization quadrupole time-of-flight mass spectrometry (nanoESI-Q-TOFMS) was used for sensitive mapping and sequencing of underivatized oligosaccharide alditols obtained from human mucins. Using subnanomolar amounts of oligosaccharides previously analyzed by nuclear magnetic resonance (NMR), series of diagnostic ions relevant to the structural characterization of O-glycans were deduced. Determination of the core type as well as positions and partial linkages of fucose residues could be readily obtained from the dominant [M+Na](+) ions. Differentiation of isomeric structures and glycosidic linkages were defined by the characteristic cross-ring (0,2)A-type cleavages in the negative ion mode. Tandem (MS/MS) mass spectra of [M-H](-) ions from sialylated or sulfated O-glycans revealed information concerning the position and linkage of such residues. These fragmentation rules were further applied in the structural determination of glycans from human colonic mucins. All these findings indicated the efficiency of ESI-Q-TOFMS for the determination of oligosaccharide composition, sequence, partial linkage and substitution, providing a wealth of structural information with sensitivity sufficient for the analysis of quantities as obtained from natural sources.     

Glycosidic linkage conformation of methyl-alpha-mannopyranoside

We study the preferred conformation of the glycosidic linkage of methyl-alpha-mannopyranoside in the gas phase and in aqueous solution. Results obtained utilizing Car-Parrinello molecular dynamics (CPMD) simulations are compared to those obtained from classical molecular dynamics (MD) simulations. We describe classical simulations performed with various water potential functions to study the impact of the chosen water potential on the predicted conformational preference of the glycosidic linkage of the carbohydrate in aqueous solution. In agreement with our recent studies, we find that results obtained with CPMD simulations differ from those obtained from classical simulations. In particular, this study shows that the trans (t) orientation of the glycosidic linkage of methyl-alpha-mannopyranoside is preferred over its gauche anticlockwise (g-) orientation in aqueous solution. CPMD simulations indicate that this preference is due to intermolecular hydrogen bonding with surrounding water molecules, whereas no such information could be demonstrated by classical MD simulations. This study emphasizes the importance of ab initio MD simulations for studying the structural properties of carbohydrates in aqueous solution.     

A polarizable force field for computing the infrared spectra of the polypeptide backbone

The shapes of the amide bands in the infrared (IR) spectra of proteins and peptides are caused by electrostatically coupled vibrations within the polypeptide backbone and code the structures of these biopolymers. A structural decoding of the amide bands has to resort to simplified models because the huge size of these macromolecules prevents the application of accurate quantum mechanical methods such as density functional theory (DFT). Previous models employed transition-dipole coupling methods that are of limited accuracy. Here we propose a concept for the computation of protein IR spectra, which describes the molecular mechanics (MM) of polypeptide backbones by a polarizable force field of "type II". By extending the concepts of conventional polarizable MM force fields, such a PMM/II approach employs field-dependent parameters not only for the electrostatic signatures of the molecular components but also for the local potentials modeling the stiffness of chemical bonds with respect to elongations, angle deformations, and torsions. Using a PMM/II force field, the IR spectra of the polypeptide backbone can be efficiently calculated from the time dependence of the backbone's dipole moment during a short (e.g., 100 ps) MD simulation by Fourier transformation. PMM/II parameters are derived for harmonic bonding potentials of amide groups in polypeptides from a series of DFT calculations on the model molecule N-methylacetamide (NMA) exposed to homogeneous external electric fields. The amide force constants are shown to vary by as much as 20% for relevant field strengths. As a proof of principle, it is shown that the large solvatochromic effects observed in the IR spectra of NMA upon transfer from the gas phase into aqueous solution are not only excellently reproduced by DFT/MM simulations but are also nicely modeled by the PMM/II approach. The tasks remaining for a proof of practice are specified.     

Electron beam modification and crosslinking: Influence of nitrile and carboxyl contents and level of unsaturation on structure and properties of nitrile rubber

The structural changes of nitrile rubber with varying nitrile contents, hydrogenated nitrile rubber and carboxylated nitrile rubber in the presence and absence of a polyfunctional monomer, namely trimethylolpropane triacrylate, at different doses of electron beam irradiation, were investigated with the help of FTIR spectroscopy (in the attenuated total reflectance mode), dynamic mechanical thermal analysis and sol–gel analysis. Solid-state NMR with gated high power decoupling technique was used to understand the mechanism of crosslinking of the irradiated samples. The allylic radicals generated in the butadiene chains react to form intermolecular crosslinkages. There was a significant decrease in the concentration of olefinic groups for the nitrile rubber on irradiation. This was also affirmed by the increase in the carbon resonances due to C–C linkages from the NMR technique, indicating more crosslinkages. The spectroscopic crosslink densities were determined and the results were compared with the swelling measurements. The variation in the crosslink clustering for rubbers with different acrylonitrile contents was explained using the NMR technique. The increase in crosslinking was also revealed by the increase in the percent gel content and dynamic storage moduli with radiation doses. The lifetime of spurs formed and the critical dose, an important criterion for overlapping of spurs, were determined for both the grafted and the ungrafted nitrile rubbers of different grades and compared using a mathematical model. The ratio of scissioning to crosslinking for nitrile rubber was determined using Charlesby–Pinner equation. The mechanical properties had also been studied for both the modified and the unmodified systems.     

Raman Optical Activity of Glucose and Sorbose in Extended Wavenumber Range

Raman optical activity (ROA) is pursued as a promising method for structural analyses of sugars in aqueous solutions. In the present study, experimental Raman and ROA spectra of glucose and sorbose obtained in an extended range (50–4000 cm⁻¹) are interpreted using molecular dynamics and density functional theory, with the emphasis on CH stretching modes. A reasonable theoretical basis for spectral interpretation was obtained already at the harmonic level. Anharmonic corrections led to minor shifts of band positions (up to 25 cm⁻¹) below 2000 cm⁻¹, while the CH stretching bands shifted more, by ∼180 cm⁻¹, and better reproduced the experiment. However, the anharmonicities could be included on a relatively low approximation level only, and they did not always improve the harmonic band shapes. The dependence on the structure and conformation shows that the CH stretching ROA spectral pattern is a sensitive marker useful in saccharide structure studies.     

Inelastic neutron scattering and DFT study of 2-amino-3-hydroxymethyl-1,3-propane diol (TRIS)

We report an inelastic neutron scattering (INS) study of 2-amino-3-hydroxymethyl-1,3-propane diol (TRIS). The assignment of the experimental vibrational spectra measured using several incident neutrons’ energies on HRMECS spectrometer has been made by means of DFT calculations. To simulate crystal environment both molecular cluster and solid state models were used. The study has been completed by an alternative approach, molecular dynamics (MD) calculations, done at the same level of the DFT theory. The INS spectra calculated with the solid state models (normal mode analysis, and MD) gave a better fit of the experiment than the cluster model. On the other hand, the peaks between 650 and 850 cm⁻¹ in the experimental INS spectra assigned to OH torsional modes were reproduced better by the cluster calculations. The nature of the stretching frequency of unusually long O–H bond (1.012 Å) was interpreted by means of MD calculations. The interpretation of the spectrum below 100 cm⁻¹ was based on Fourier transform of the velocity autocorrelation function of centre of mass of a molecule of TRIS.     

Identification of active sites of biomolecules. 1. Methyl-alpha-mannopyranoside and Fe(III)

Car-Parrinello molecular dynamics (CPMD) simulations, DFT chemical reactivity index calculations, and mass spectrometric measurements are combined in an integrated effort to elucidate the details of the coordination of a transition-metal ion to a carbohydrate. The impact of the interaction with the FeIII ion on the glycosidic linkage conformation of methyl-alpha-d-mannopyranoside is studied by classical molecular dynamics (MD) and CPMD simulations. This study shows that FeIII interacts with specific hydroxyl oxygen atoms of the carbohydrate, affecting the ground state carbohydrate conformation. These conformational details are discussed in terms of a set of supporting experiments involving electrospray ionization mass spectrometry, and CPMD simulations clearly indicate that the specific conformational preference is due to intramolecular hydrogen bonding. Classical MD simulations proved insensitive to these important chemical properties. Thus, we demonstrate the importance of chemical reactivity calculations and CPMD simulations in predicting the active sites of biological molecules toward metal cations.     

Calculation of Raman optical activity spectra of methyl-β-D-glucose incorporating a full molecular dynamics simulation of hydration effects

We report calculations of the Raman and Raman optical activity (ROA) spectra of methyl-β-D-glucose utilizing density functional theory combined with molecular dynamics (MD) simulations to provide an explicit hydration environment. This is the first report of such combination of MD simulations with ROA ab initio calculations. We achieve a significant improvement in accuracy over the more commonly used gas phase and polarizable continuum model (PCM) approaches, resulting in an excellent level of agreement with the experimental spectrum. Modeling the ROA spectra of carbohydrates has until now proven a notoriously difficult challenge due to their sensitivity to the effects of hydration on the molecular vibrations involving each of the chiral centers. The details of the ROA spectrum of methyl-β-D-glucose are found to be highly sensitive to solvation effects, and these are correctly predicted for the first time including those originating from the highly sensitive low frequency vibrational modes. This work shows that a thorough consideration of the role of water is pivotal for understanding the vibrational structure of carbohydrates and presents a new and powerful tool for characterizing carbohydrate structure and conformational dynamics in solution.     

MD Calculations on Nystose Combined with NMR Spectroscopy on Inulin Related Oligosaccharides

Abstract

Molecular Dynamics (MD) calculations have been performed on nystose in water. According to these calculations the glycosidic linkages of the molecule are flexible. Structures obtained with MD calculations are compared with NMR data of several inulin related oligosaccharides and inulin, resulting in a model for the conformation of their fructofuranosyl residues. To extend the set of available NMR data of inulin related oligosaccharides, the complete assignment of the ¹H and ¹³C NMR signals of β-D-fructofuranosyl-(2->l)-ß-D-fructofuranosyl-(2->l)-ß-D-fructofuranosyl-(2->l)-ß-D-fructofuranosyl-(2->l)-α-D-glucopyranoside has been given here, using several 2D homo- and heteronuclear NMR experiments. Accurate coupling constants have been obtained by simulation of the 600 MHz 1D NMR spectra.     

Binding energies of five molecular pincers calculated by explicit and implicit solvent models

Molecular pincers or tweezers are designed to hold and release the target molecule. Potential applications involve drug distribution in medicine, environment technologies, or microindustrial techniques. Typically, the binding is dominated by van der Waals forces. Modeling of such complexes can significantly enhance their design; yet obtaining accurate complexation energies by theory is difficult. In this study, density functional theory (DFT) computations combined with dielectric continuum solvent model are compared with the potential of mean force approach using umbrella sampling and the weighted histogram analysis method (WHAM) with molecular dynamics (MD) simulations. For DFT, functional and basis set effects are discussed. The computed results are compared to experimental data based on NMR spectroscopic measurements of five synthesized tweezers based on the Tröger's basis. Whereas the DFT computations correctly provided the observed trends in complex stability, they failed to produce realistic magnitudes of complexation energies. Typically, the binding was overestimated by DFT if compared to experiment. The simpler semiempirical PM6‐DH2X scheme proposed lately yielded better magnitudes of the binding energies than DFT but not the right order. The MD‐WHAM simulations provided the most realistic Gibbs binding energies, although the approximate MD force fields were not able to reproduce completely the ordering of relative stabilities of model complexes found by NMR. Yet the modeling provides interesting insight into the complex geometry and flexibility and appears as a useful tool in the tweezers' design. © 2012 Wiley Periodicals, Inc.     

Conformational differences between O- and C-glycosides: the alpha-O-man-(1-->1)-beta-Gal/alpha-C-Man-(1-->1)-beta-Gal case--a decisive demonstration of the importance of the exo-anomeric effect on the conformation of glycosides

The conformational behavior of alpha-O-Man-(1-->1)-beta-Gal (1) and its C-analogue (2) has been studied using J/NOE NMR data, molecular mechanics, molecular dynamics, and ab initio calculations. The population distribution around the glycosidic linkages of 1 and 2 is rather different, especially for the alpha-Man linkage. A lower limit for the exo-anomeric effect in water has been experimentally determined.     

Interpretation of the IR and Raman spectra of morin by density functional theory and comparative analysis

Density functional theory calculations, with M05-2X functional and 6-311++G(d,p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure and spectroscopic characteristics of morin, a bioflavonoid molecule known for its antiproliferative, antitumor, and anti-inflammatory effects. Detailed vibrational spectral analysis and the assignments of the bands, done on the best-fit basis comparison of the experimentally obtained and theoretically calculated IR and Raman spectra, match quite well indicating DFT calculations as very accurate source of normal mode assignments. The assignment of the most prominent normal modes of morin is qualitatively verified through comparative spectral analysis with quercetin, a structurally isomeric molecule of morin which differs only by the substitution pattern of the B ring. Performed comparative analysis reflects quite accurately all the structural differences between the investigated molecules additionally proving the applied theoretical method.     

Midkine Interaction with Chondroitin Sulfate Model Synthetic Tetrasaccharides and Their Mimetics: The Role of Aromatic Interactions

Midkine (MK) is a neurotrophic factor that participates in the embryonic central nervous system (CNS) development and neural stem cell regulation, interacting with sulfated glycosaminoglycans (GAGs). Chondroitin sulfate (CS) is the natural ligand in the CNS. In this work, we describe the interactions between a library of synthetic models of CS-types and mimics. We did a structural study of this library by NMR and MD (Molecular Dynamics), concluding that the basic shape is controlled by similar geometry of the glycosidic linkages. Their 3D structures are a helix with four residues per turn, almost linear. We have studied the tetrasaccharide-midkine complexes by ligand observed NMR techniques and concluded that the shape of the ligands does not change upon binding. The ligand orientation into the complex is very variable. It is placed inside the central cavity of MK formed by the two structured beta-sheets domains linked by an intrinsically disordered region (IDR). Docking analysis confirmed the participation of aromatics residues from MK completed with electrostatic interactions. Finally, we test the biological activity by increasing the MK expression using CS tetrasaccharides and their capacity in enhancing the growth stimulation effect of MK in NIH3T3 cells.     

Structural effects on the electronic absorption properties of 5,6-dihydroxyindole oligomers: the potential of an integrated experimental and DFT approach to model eumelanin optical properties

Elucidation of the relationships between structural features and UV-visible absorption properties of 5,6-dihydroxyindole oligomers is an essential step towards an understanding of the unique optical properties of eumelanins. Herein, we report the first combined experimental and density functional theory (DFT) investigation of the 5,6-dihydroxyindole oligomers so far isolated. 2,2'-Biindolyl 2 and the 2,4'-biindolyl 3 absorb at longer wavelengths relative to 2,7'-biindolyl 4 and their spectra were well predicted by DFT analysis. The absorption bands of 2,4':2',4'- and 2,4':2',7'-triindolyls 5 and 6 also fall at different wavelengths and can be interpreted by DFT simulations as being due to a combination of two main separate transitions. Tetramer 7, in which two 2,4'-biindolyl units are linked through a 2,3'-connection, exhibits a broad chromophore extending over the entire UV range without well defined absorption maxima. Within the dimer-tetramer range examined, three key points emerge: (1) an increase in oligomer chain length does not result in any regular and predictable bathochromic shift; (2) a marked broadening of the absorption bands occurs when going from the monomer to the tetramer structure; and (3) the mode of coupling of the indole units is a crucial, hitherto unrecognized, structural parameter affecting the electronic absorption properties of 5,6-dihydroxyindole oligomers. It is concluded that use of experimentally characterized oligomeric scaffolds as a basis for DFT calculations is a most promising approach to building reliable structural models for studies of eumelanins optical properties.