Molecular Conformation In Solution Research Articles

Ensemble determination by NMR data deconvolution.

Nuclear magnetic resonance (NMR)is the spectroscopic technique of choice for determining molecular conformations in solution at atomic resolution. As solution NMR spectra are rich in structural and dynamic information, the way in whichthe data should be acquired and handled to deliver accurate ensembles is not trivial. This Review provides a guide to the NMRexperiment selection and parametrization process, the generation of viable theoretical conformer pools and the deconvolution of time-averaged NMR data into a conformer ensemble that accurately represents a flexible molecule in solution. In addition to reviewing the key elements of solution ensemble determination of flexible mid-sized molecules, the feasibility and pitfalls of data deconvolution are discussed with a comparison of the performance of representative algorithms.

Selective crystallization of gamma glycine for NLO applications using magnesium sulfate (MgSO4) as an additive

Abstract Crystallization of γ-glycine in the presence of selected concentration (9 g/mL) of tailor-made additive magnesium sulfate heptahydrate salt (MgSO4·7H2O) has been studied at ambient temperature by adopting slow solvent evaporation procedure. The morphological modifications of glycine crystals grown from pure aqueous solutions of glycine and from glycine solutions containing magnesium species in the amount of 0.1 g/mL to 16 g/mL have been investigated thoroughly. The crystalline nature and phase identification of the crystalline material were confirmed by X-ray powder diffraction and SXRD studies. NMR studies revealed the information about the molecular conformation in solution, phase changes, functional groups and chemical environment. FT-IR spectra revealed distinct difference between α and γ-glycine polymorphs in the region around 880 cm−1 to 930 cm−1. The grown γ-glycine crystal had a lower cut-off value at 200 nm and the bandgap value evaluated from the Tauc plot was found to be 5.83 eV. The marked differences between α and γ-polymorphs of glycine were also revealed by DSC thermograms. The mechanical strength of the γ-glycine crystal was studied with the help of Vickers microhardness instrument. Kurtz-powder NLO study proved the generation of second harmonics (i.e. green light emission) in the grown γ-glycine crystal and its efficiency was calculated as 1.44 times better than that of the reference material potassium dihydrogen phosphate.

Solvent Quality Controls Macromolecular Structural Dynamics of a Dendrimeric Hydrogenase Model.

We report a spectroscopic investigation of the ultrafast dynamics of the second-generation poly(aryl ether) dendritic hydrogenase model using two-dimensional infrared (2D-IR) spectroscopy to probe the metal carbonyl vibrations of the dendrimer and a reference small molecule, [Fe(μ-S)(CO)3]2. We find that the structural dynamics of the dendrimer are reflected in a slow phase of the spectral diffusion, which is absent from [Fe(μ-S)(CO)3]2, and we relate the slow phase to the quality of the solvent for poly(aryl ether) dendrimers. We observe a solvent-dependent modulation of the initial phase of vibrational relaxation of the carbonyl groups, which we attribute to an inhibition of solvent assistance in the intramolecular vibrational redistribution process for the dendrimer. There is also a clear solvent dependence of the vibrational frequencies of both the dendrimer and [Fe(μ-S)(CO)3]2. Our data represent the first 2D-IR study of a dendritic complex and provide insight into the solvent dependence of molecular conformation in solution and the ultrafast dynamics of moderately sized, conformationally mobile compounds.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure.

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile<ethyl acetate<n-propanol<toluene. The combined DFT and MD modelling results show that in acetonitrile, ethyl acetate and n-propanol the nucleation difficulty is a function of the strength of solvent-solute interaction, with emphasis on the interaction with specific H-bonding polar sites of importance in the crystal structure. A clear exception from this rule is the most difficult nucleation in toluene despite the weakest solvent-solute interactions. However molecular dynamics modelling predicts that tolbutamide assumes an intramolecularly H-bonded conformation in toluene, substantially different from and more stable than the conformation in the crystal structure, and thus presenting an additional barrier to nucleation. This explains why nucleation in toluene is the most difficult and why the relatively higher propensity for aggregation of tolbutamide molecules in toluene solution, as observed with FTIR spectroscopy, does not translate into easier nucleation. Thus, our combined experimental and molecular modelling study suggests that the solvent can influence on the nucleation not only via differences in the desolvation but also through the influence on molecular conformation.

Dihydrogen contacts observed by through-space indirect NMR coupling.

"Through-space" indirect spin-spin couplings between hydrogen atoms formally separated by up to 18 covalent bonds have been detected by NMR experiments in model helical molecules. It is demonstrated that this coupling can provide crucial structural information on the molecular conformation in solution. The coupling pathways have been visualised and analysed by computational methods. The conformational dependence of the coupling is explained in terms of orbital interactions.

Towards an understanding of crystallization from solution. DFT studies of multi-component serotonin crystals

A potential energy surface (PES) has been calculated for the protonated serotonin (5-HT) molecule in aqueous media. Three pairs of symmetrically equivalent minima were located using fully relaxed optimization at B3LYP/6-31G(d,p) level of theory. Insensitivity to basis set was verified over a range of different functionals and levels of theory. All 9 transition structures were found using the QST3 method with ansatz structures taken directly from the result of the calculated PES. Energies associated with conformational changes of protonated 5-HT in aqueous media were calculated and found to vary between 6 and 23kJmol−1. Lattice energies of serotonin picrate monohydrate and serotonin adipate were calculated as −741.7 and −716.9kJmol−1, respectively, and compared to conformational energies to consider the relative importance of each interaction type. The study contributes to achieving better insight into the importance of molecular conformations in solution as a precursor for the formation of the final crystal structure.

On the connection between nonmonotonic taste behavior and molecular conformation in solution: The case of rebaudioside-A.

The diterpene steviol glycoside, rebaudioside A, is a natural high potency non-caloric sweetener extracted from the leaves of Stevia rebaudiana. This compound shows a parabolic change in sweet taste intensity with temperature which contrasts with the general finding for other synthetic or natural sweeteners whose sweet taste increases with temperature. The nonmonotonic taste behavior was determined by sensory analysis using large taste panels. The conformational landscape of rebaudioside A was established at a range of temperatures by means of nuclear magnetic resonance and molecular dynamics simulation. The relationship between various conformations and the observed sweetness of rebaudioside A is described.

Conjugation-Induced Rigidity in Twisting Molecules: Filling the Gap Between Aggregation-Caused Quenching and Aggregation-Induced Emission.

Conjugation-induced rigidity in twisting molecules provides a new facile but effective avenue toward solution and solid dual-state efficient luminogens. While conjugation rigidifies the molecular conformations in solution, the twisting structure prevents or alleviates detrimental close molecular packing in the solid states, thus synergistically yielding high efficiencies in both solution and solid states.

Synthesis, Characterization, Electrochemistry, and Computational Studies of Ferrocenyl-Substituted Siloles

Ferrocenylsiloles of the type 2,5-Fc2-3,4-Ph2-cC4SiR2 (3a, R = Me; 3b, R = Ph) have been prepared by reductive cyclization from diethynylsilanes, followed by ferrocenylation using the Negishi C,C cross-coupling protocol with the silole ring serving as either the vinyl halogenide species or as the zinc organic component and the complementary functionality introduced on the ferrocenyl moiety. The electrochemical behavior of these silacyclic-bridged bis(ferrocenyl) complexes was investigated by cyclic and square wave voltammetry, and the nature of the redox products was studied by in situ UV–vis–near-IR spectroelectrochemical measurements. 3a,b each undergo two sequential ferrocenyl-based redox processes, the separation of which (ΔE°′ = ΔE2°′ – ΔE1°′ = 300 mV (3a), 280 mV (3b)) is in the range of structural similar systems such as 2,5-diferrocenyl-1-phenyl-1H-phosphole (280 mV) and 2,5-diferrocenylfuran (290 mV). Interestingly, the more electron rich silole 3b, in comparison to 3a, shows a modestly lower redox separation between the individual ferrocenyl oxidation processes, which may be due to the capacity of this group to shield the effect of an adjacent positive charge. An intervalence charge transfer (IVCT) absorption was found in the in situ NIR spectra of [3a]+ and [3b]+, the analysis of which is consistent with a moderate electronic interaction between the iron atoms through the cis-diene-like fragment of the silole bridge, allowing their description as Robin and Day class II mixed-valence systems. These conclusions are supported by results from quantum chemical calculations, which together with NMR studies of 3b, also reveal the likely presence of a range of molecular conformations in solution.

A novel approach to understand the nucleation kinetics of α and γ polymorphs of glycine from aqueous solution in the presence of a selective additive through charge compensation mechanism

Nucleation of either the α or γ polymorph of glycine takes place by the dominant existence of dimer or monomer molecular conformations in solution. The effect of the selective additive sodium nitrate on the nucleation behaviour of the α and γ polymorphs of glycine is investigated both by experimental and analytical approaches. Experimentally, in situ nucleation tests were performed to measure the induction period of nucleation, type of nucleation and their proportionate appearance in the presence of different concentrations of the additive in solution. The internal structure of the nucleated crystallites was confirmed by single crystal X-ray diffraction analysis. Nucleation of α and γ glycine takes place through a charge compensation mechanism. The incorporation of various concentrations of the additive changes the supersaturation of the system, which in turn changes the induction period of nucleation. Nucleation of the γ polymorph occurs at a critical concentration of the additive. Analytically, the nucleation parameters, such as interfacial energy, volume excess free energy, critical radius, critical energy barrier and nucleation rate of the α and γ polymorphs, were estimated based on classical nucleation theory from the experimentally measured induction periods. Variation in these theoretically deduced nucleation parameters with respect to the supersaturation in the system coincides well with the experimentally observed variation of these parameters during the kinetic processes observed within the experimental conditions. This correlation between the experimental and theoretical evidences provides a deeper insight in enabling us to have a clear idea as to what exactly happens inside the system. Moreover, the probability nucleation ratio of the α and γ polymorphs, estimated by powder X-ray diffraction and DSC followed by their structural confirmations, coincides very well with the experimentally observed values.

Coil-to-rod conformational transition and single chain structure of graft copolymer by tuning the graft density

The chain conformation and individual chain structures of the graft copolymers ethyl cellulose grafting poly (acrylic acid) (EC-g-PAA) were investigated by laser light scattering (LLS) and atom force microscopy (AFM). The EC-g-PAA graft copolymers with two different side chain lengths and side chain grafting densities were synthesized via atom transfer radical polymerization (ATRP) from ethyl cellulose as the backbone. The graft copolymer molecules are adsorbed on the mica surface, and the observed single molecule structures by AFM reflect the molecular conformation in solution. An increase of the graft density of the graft copolymer induces the conformational transition due to the repulsion between side chains from coil to rod conformation. The observed disclike and rodlike single chain structures response to the coil and rod conformations, respectively. The results provide a direct visual experimental evidence of chain conformational and single chain structural transitions for graft copolymers in common solvents induced by graft density.

Polymorph Formation and Nucleation Mechanism of Tolfenamic Acid in Solution: An Investigation of Pre-nucleation Solute Association

Crystallization from solution involves nucleation and growth; growth conditions greatly influence self-association behaviors of solute molecules in these steps, affecting crystal packing of organic molecules. We examined the role of pre-nucleation association to provide insights into the mutual influence between molecular conformation in solution and packing in the solid state. Crystallization experiments of tolfenamic acid were conducted in ethanol under different supersaturation conditions. UV spectroscopy was performed to study self-association of solute molecules in ethanol as a function of concentration. Intermolecular interaction energies of tolfenamic acid dimers were calculated with quantum mechanical methods. As supersaturation increased, growth of the most stable polymorph outpaced the metastable one, contradicting Ostwald's Rule of Stages. UV spectroscopy measurement suggests solute molecules exist as hydrogen-bonded dimers and more dimers form as total concentration increases. Hydrogen bonding in the most stable form is significantly stronger than that in the metastable form. With the fact that molecular conformation is different in the two polymorphs, as concentration increases, solute molecules rearrange their conformations to form stronger hydrogen-bonded dimers in solution, resulting in nucleation of the most stable form.

Conformationally Controlled Electron Delocalization in n‐Type Rods: Synthesis, Structure, and Optical, Electrochemical, and Spectroelectrochemical Properties of Dicyanocyclophanes

A series of dicyanobiphenylcyclophanes 1-6 with various π-backbone conformations and characteristic n-type semiconductor properties is presented. Their synthesis, optical, structural, electrochemical, spectroelectrochemical, and packing properties are investigated. The X-ray crystal structures of all n-type rods allow the systematic correlation of structural features with physical properties. In addition, the results are supported by quantum mechanical calculations based on density functional theory. A two-step reduction process is observed for all n-type rods, in which the first step is reversible. The potential gap between the reduction processes depends linearly on the cos(2) value of the torsion angle φ between the π-systems. Similarly, optical absorption spectroscopy shows that the vertical excitation energy of the conjugation band correlates with the cos(2) value of the torsion angle φ. These correlations demonstrate that the fixed intramolecular torsion angle φ is the dominant factor determining the extent of electron delocalization in these model compounds, and that the angle φ measured in the solid-state structure is a good proxy for the molecular conformation in solution. Spectroelectrochemical investigations demonstrate that conformational rigidity is maintained even in the radical anion form. In particular, the absorption bands corresponding to the SOMO-LUMO+i transitions are shifted bathochromically, whereas the absorption bands corresponding to the HOMO-SOMO transition are shifted hypsochromically with increasing torsion angle φ.

Effect of Molecular Conformations on the Adsorption Behavior of Gold-Binding Peptides

Despite extensive recent reports on combinatorially selected inorganic-binding peptides and their bionanotechnological utility as synthesizers and molecular linkers, there is still only limited knowledge about the molecular mechanisms of peptide binding to solid surfaces. There is, therefore, much work that needs to be carried out in terms of both the fundamentals of solid-binding kinetics of peptides and the effects of peptide primary and secondary structures on their recognition and binding to solid materials. Here we discuss the effects of constraints imposed on FliTrx-selected gold-binding peptide molecular structures upon their quantitative gold-binding affinity. We first selected two novel gold-binding peptide (AuBP) sequences using a FliTrx random peptide display library. These were, then, synthesized in two different forms: cyclic (c), reproducing the original FliTrx gold-binding sequence as displayed on bacterial cells, and linear (l) dodecapeptide gold-binding sequences. All four gold-binding peptides were then analyzed for their adsorption behavior using surface plasmon resonance spectroscopy. The peptides exhibit a range of binding affinities to and adsorption kinetics on gold surfaces, with the equilibrium constant, Keq, varying from 2.5x10(6) to 13.5x10(6) M(-1). Both circular dichroism and molecular mechanics/energy minimization studies reveal that each of the four peptides has various degrees of random coil and polyproline type II molecular conformations in solution. We found that AuBP1 retained its molecular conformation in both the c- and l-forms, and this is reflected in having similar adsorption behavior. On the other hand, the c- and l-forms of AuBP2 have different molecular structures, leading to differences in their gold-binding affinities.

Structure and properties of regenerated Antheraea pernyi silk fibroin in aqueous solution

Antheraea pernyi silk fibroin fibers were dissolved by aqueous lithium thiocyanate to obtain regenerated A. pernyi silk fibroin solution. By means of circular dichroism, 13C NMR and Raman spectroscopy, the molecular conformation of regenerated A. pernyi silk fibroin in aqueous solution was investigated. The relationship of environmental factors and sol–gel transformation behavior of regenerated A. pernyi silk fibroin was also studied. The molecular conformations of regenerated A. pernyi silk fibroin mainly were α-helix and random coil in solution. There also existed a little β-sheet conformation. It was obviously different with Bombyx mori silk fibroin, whose molecular conformation in solution was only random coil but no α-helix existence. With the increase of temperature and solution concentration and with the decrease of solution pH value, the gelation velocity of regenerated A. pernyi silk fibroin solution increased. Especially, it showed that A. pernyi silk fibroin was more sensitive to temperature than B. mori silk fibroin during the sol–gel transformation. The velocity increased obviously when the temperature was above 30 °C. During the sol–gel transformation, the molecular conformation of regenerated A. pernyi silk fibroin changed from random coil to β-sheet structure. The results of these studies provided important insight into the preparation of new biomaterials by silk fibroin protein.

Cascade of coil-globule conformational transitions of single flexible polyelectrolyte molecules in poor solvent.

We show that hydrophobic flexible polyelectrolyte molecules of poly(2-vinylpyridine) and poly(methacryloyloxyethyl dimethylbenzylammonium chloride) are trapped and frozen due to adsorption on the mica surface, and the observed AFM single molecule structures reflect the molecular conformation in solution. An increase of the ionic strength of the solution induces the cascade of abrupt conformational transitions due to the intrachain segregation from elongated coil to compact globule conformations through intermediate pearl necklace-globule conformations with different amounts of beads per chain. The length of the necklaces and the number of beads decrease, while the diameter of beads increases with the increase of ionic strength. Coexistence at the same time of extended coils, necklaces with different amounts of beads, and compact globules indicates the cascade of the first-order-type phase transitions.

Small-Angle X-ray Scattering Studies of Poly(arylethinylene): Molecular Conformation in Solution and Orientational Ordering in Rod−Coil Ionomer Blends

Poly(pyridyl/phenyl-ethinylene) polymers of tuned rigidity/flexibility were synthesized and their molecular conformations in solution determined by small-angle X-ray scattering. These polymers were used as molecularly dispersed reinforcing components in ionomer blends with partially sulfonated polystyrene. Homogeneous ionomer blends were formed by acid−base interactions between the two blend components. Small-angle X-ray scattering revealed that in the case of rodlike or semiflexible poly(pyridyl/phenyl-ethinylenes) an elongation-induced orientational ordering is obtained. However, blend samples prepared with flexible poly(pyridyl/phenyl-ethinylene) polymers do not show any observable orientation. The orientation parameter varied systematically with the rigidity/flexibility of the reinforcing component, as did the Young modulus determined from stress−strain measurements.

3-Aryloxypropiononitriles Intermediates: Crystal and Molecular Structure of 2- and 4-(2-Bromoethoxy)diphenylmethanes

The crystal structure of 2- and 4-(2-bromoethoxy)diphenylmethanes (I and II respectively), intermediates in a novel synthesis of substituted 3-aryloxypropiononitriles, have been determined by single crystal X-ray diffraction at room temperature (r.t.) and at 150K. No significant changes in the crystal structure of I and II have been observed in going from r.t. to 150K. In both compounds the bromoethoxy group presents a gauche conformation and shows a short Br...O intramolecular interaction that allows to explain the very good reaction yields obtained in the novel synthesis. The three-dimensional structure of I is stabilized by two intermolecular hydrogen bonds and that of II by six. This difference in the crystal packing of I and II explains the variation in the m.p. The analysis of 1 H and 13 C NMR spectra suggests that the molecular conformations in solution are similar to those found in solid state.

Proton Nuclear Magnetic Resonance Studies of the Structure of Neuropeptide V and its Analogs

NPY is regarded as the most common peptide in the central and peripheral nervous systems and heart of many mammalian species including man. It has been found to perform critical regulatory functions in behavior, control of the cardiovascular system, memory processing etc. Development of highly selective and potent antagonists will allow better understanding of the pathological and physiological roles of NPY. In the process of designing potent receptor antagonists, which are essential in detailed studies of structure function relationships, NMR has played a major role in determining the solution structure of NPY and its analogs. Sequential proton NMR assignments have been made using several two dimensional techniques, COSY, DQFCOSY, HOHAHA, NOESY and ROESY. NMR has served as a complementary technique to X-ray since solid state studies do not necessarily always provide the correct picture of molecular conformation in solution, particularly for small flexible peptides. NPY consists of an a-helix domain (residues 15-35) with a hinge at position 27 and a polyproline stretch (residues 1--10) connected by a tight hairpin (residues 11-14). NMR has provided critical information in demonstrating formation of NPY dimers in aqueous media. Based on these results, recent designs have shown that high affinity analogs can be developed through C-terminal analogs dimerized with disulfide or lactam bridges. This review surveys NMR studies of NPY and its analogs with particular reference to the use of NMR data in molecular modeling of the solution structure.

Influence of the degree of acetylation of o‐cresol resin on its molecular conformation in solution

Abstracto‐Cresol‐formaldehyde resin (OC) and five kinds of acetylated OC (AC‐X‐OC; X is the degree of acetylation) were prepared. The Θ‐temperature for each resin was determined by means of the Shultz‐Flory method, and their molecular conformations in both tetrahydrofuran (THF) and Θ‐solvent were estimated from the values of the exponents in the Mark–Houwink–Sakurada equations. The effect of the degree of acetylation on the exponent was negligible in THF, but was remarkable in Θ‐solvent. In THF, the molecular chains of these resins are relatively extended, because the hydrogen bond between phenolic hydroxyl groups is loosely formed. In Θ‐solvent, however, the molecular conformation is compact and the resins are considered to form a pseudo cross‐linked network structure through inter‐ and/or intra‐molecular hydrogen bonds. The Mark–Houwink–Sakurada equation for AC‐100‐OC in 2‐ethoxyethanol at 92.0°C was found to be [η]θ = 0.0773 M̄0.50n, where [η]0 is the limiting viscosity number under the Θ‐condition, and M̄n is the number‐average molecular weight. The unperturbed dimension, (〈r20〉/M̄n)1/2, 〈r20〉 being the unperturbed mean square end‐to‐end distance, for AC‐100‐OC was found to be 0.659×10−8 cm g−1/2 mol1/2.