Basic Structural Motif Research Articles

Toward determining amyloid fibril structures using experimental constraints from Raman spectroscopy

We present structural models for three different amyloid fibril polymorphs prepared from amylin20–29 (sequence SNNFGAILSS) and amyloid-β25–35 (Aβ25–35) (sequence GSNKGAIIGLM) peptides. These models are based on the amide C=O bond and Ramachandran ψ-dihedral angle data from Raman spectroscopy, which were used as structural constraints to guide molecular dynamics (MD) simulations. The resulting structural models indicate that the basic structural motif of amylin20–29 and Aβ25–35 fibrils is extended β-strands. Our data indicate that amylin20–29 forms both antiparallel and parallel β-sheet fibril polymorphs, while Aβ25–35 forms a parallel β-sheet fibril structure. Overall, our work lays the foundation for using Raman spectroscopy in conjunction with MD simulations to determine detailed molecular-level structural models of amyloid fibrils in a manner that complements gold-standard techniques, such as solid-state nuclear magnetic resonance and cryogenic electron microscopy.

New Polymorphic Modifications of 6-Methyluracil: An Experimental and Quantum Chemical Study.

Polymorphism of 6-methyluracil, which affects the regulation of lipid peroxidation and wound healing, has been studied by experimental and quantum chemical methods. Two known polymorphic modifications and two new crystalline forms were crystallized and characterized by single crystal and powder X-ray diffraction (XRD) methods as well as by the differential scanning calorimetry (DSC) method and infrared (IR) spectroscopy. The calculations of pairwise interaction energies between molecules and lattice energies in periodic boundary conditions have shown that the polymorphic form 6MU_I used in the pharmaceutical industry and two new forms 6MU_III and 6MU_IV, which can be formed due to temperature violations, may be considered as metastable. The centrosymmetric dimer bound by two N-H···O hydrogen bonds was recognized as a dimeric building unit in all of the polymorphic forms of 6-methyluracil. Four polymorphic forms have a layered structure from the viewpoint of interaction energies between dimeric building units. The layers parallel to the (100) crystallographic plane were recognized as a basic structural motif in the 6MU_I, 6MU_III, and 6MU_IV crystals. In the 6MU_II structure, a basic structural motif is a layer parallel to the (001) crystallographic plane. The ratio between the interaction energies within the basic structural motif and between neighboring layers correlates with the relative stability of the studied polymorphic forms. The most stable polymorphic form 6MU_II has the most anisotropic "energetic" structure, while the interaction energies in the least stable form 6MU_IV are very close in various directions. The modeling of shear deformations of layers in the metastable polymorphic structures has not revealed any possibility of these crystals to be deformed under external mechanical stress or pressure influence. These results allow the use of metastable polymorphic forms of 6-methyluracil in the pharmaceutical industry without any limitations.

Intriguing π-interactions involving aromatic neutrals, aromatic cations and semiconducting behavior in a pyridinium-carboxylate salt

A new pyridinium-carboxylate salt (1) has been synthesized and characterized by elemental analysis, spectroscopy, electrical studies, and single-crystal X-ray diffraction. X-ray structure of 4,4′-oxybis(benzoic acid) with 4-(Dimethylamino)pyridine is stabilized through hydrogen bonds, C‒H···π, and numerous π-interactions together with π···π, π···π+, and π+···π+stacking. The cooperativity of the weak noncovalent interactions has been explored well that plays a crucial role in building diverse extended supramolecular frameworks. The hydrogen bonds dictate the basic structural motifs representing the supramolecular association. However, the cooperativity of the weak noncovalent contacts plays a significant role in constructing the final solid-state structure. The entire assembly produces a rare combination of π···π/π···π+/π+···π+/π+···π extended network. The binding energies of the noncovalent interactions have anticipated the usage of DFT calculations. Intricate combinations of these noncovalent interactions are characterized through computational studies by using Bader's theory of “Atoms-in-Molecules” (AIM) and “noncovalent interaction” (NCI) plot index. The evaluation of topological parameters at (3, -1) BCPs ensured the ‘closed-shell’ nature of the intermolecular interactions. By employing Tauc's plot, the optical band gap was calculated from UV–Vis spectroscopy. A device was fabricated for the analysis of I-V characteristics of the compound. An impedance study was carried out and consequently, Nyquist plot was represented for the further investigation of the semiconducting behavior of the compound.

Crystallization, structural study and analysis of intermolecular interactions of a 2-aminobenzoxazole–fumaric acid molecular salt

The new organic salt, 2-aminobenzoxazol-3-ium 3-carboxyprop-2-enoate, C7H7N2O+·C4H3O4 −, of the two bioactive compounds 2-aminobenzoxazole and fumaric acid, crystallizes in the orthorhombic space group Pbca using classical evaporation of their solution in water. The usual topological analysis revealed four classical (N—H...O and O—H...O) and two non-classical (C—H...O) hydrogen bonds in the structure. Stacking was found as well for a pair of 2-aminobenzoxazolium cations. A Hirshfeld surface analysis including the two-dimensional fingerprint plots was performed to define the residual π–π interactions and to quantify the influences of different types of interactions by means of topological analysis. Analysis of the pairwise interaction energies was used to prove the formation of the corrugated paired layers of cation–anion dimers parallel to the plane (001) as a basic structural motif in the topological, as well as in the energetic structure of the crystal. It showed that the layers are connected by the hydrogen bonds inside and by stacking and π–π interactions and general dispersion between them.

Local Cluster Distortions in Amorphous Organotin Sulfide Compounds and Their Influence on the Nonlinear Optical Properties

AbstractThe local structure of four amorphous organotin sulfide compounds is investigated by X‐ray absorption spectroscopy. These compounds exhibit a nonlinear optical (NLO) response upon irradiation with a continuous‐wave near‐infrared laser. Their basic structural motif is a hetero‐adamantane cluster with different organic substituent, but depending on the morphology of the compound and the choice of the organic substituent, the nature of the NLO response changes to either a second harmonic generation or the generation of a supercontinuum, potentially appearing as white light. The structural results provide an experimental evidence that the nature of the NLO properties is tied to distortions occurring at the cluster core, with almost ideal clusters in compounds that show second harmonic generation, and strongly distorted clusters in the case of compounds that generate a supercontinuum. These distortions may enable a closer proximity of the cluster cores, altering the intermolecular order, and thereby influencing the NLO response.

Coherent interfaces govern direct transformation from graphite to diamond

Understanding the direct transformation from graphite to diamond has been a long-standing challenge with great scientific and practical importance. Previously proposed transformation mechanisms1–3, based on traditional experimental observations that lacked atomistic resolution, cannot account for the complex nanostructures occurring at graphite−diamond interfaces during the transformation4,5. Here we report the identification of coherent graphite−diamond interfaces, which consist of four basic structural motifs, in partially transformed graphite samples recovered from static compression, using high-angle annular dark-field scanning transmission electron microscopy. These observations provide insight into possible pathways of the transformation. Theoretical calculations confirm that transformation through these coherent interfaces is energetically favoured compared with those through other paths previously proposed1–3. The graphite-to-diamond transformation is governed by the formation of nanoscale coherent interfaces (diamond nucleation), which, under static compression, advance to consume the remaining graphite (diamond growth). These results may also shed light on transformation mechanisms of other carbon materials and boron nitride under different synthetic conditions.

Quantum Chemical Study on Mefenamic Acid Polymorphic Forms.

Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the centrosymmetric dimer formed due to two O–H···O hydrogen bonds is a complex building unit in all of the polymorphic structures under study. On the basis of an analysis of the pairwise interaction energies between molecules, the polymorphic forms I and II are classified as columnar-layered while the polymorphic form III has a columnar structure. The stabilities of the three polymorphic forms of mefenamic acid under ambient conditions (I > II > III) correlate with the degree of anisotropy of the interaction energies between columns (primary basic structural motifs) formed due to stacking interactions. The shear deformation modeling of strongly bound layers in all of the polymorphic structures has not revealed any possibility for deformation of the crystal structure. The construction of the shift energy profiles and calculation of the energy barriers for the displacement along the (100) crystallographic plane in the [100], [010], and [011] crystallographic directions make it possible to explain the experimental data obtained for commercially available polymorphic structure I in a diamond anvil cell. The absence of any local minimum near the starting point on the shift energy profile and the extremely high energy barrier can be considered as criteria for the impossibility of a crystal structure deformation under pressure.

Local Structure of Amorphous Organotin Sulfide Clusters by Low‐Energy X‐Ray Absorption Fine Structure

The local structure of four amorphous organotin sulfide compounds exhibiting nonlinear optical (NLO) properties is investigated by low‐energy X‐ray absorption spectroscopy (XANES and EXAFS). The basic structural motif of a heteroadamantane cluster with different organic substituents is confirmed by the experiments and by comparison with computer simulations of the near‐edge structure. Essential information is obtained on a special role of the nonaromatic but electron‐rich cyclopentadienyl substituents, which are able to affect the structure of the heteroadamantane cluster core. The EXAFS fits also indicate a structural distinction between two groups within these compounds, which exhibit fundamentally different NLO responses: compounds that show a second harmonic generation can be described well using the single‐molecule approach, whereas the compounds exhibiting the generation of a supercontinuum manifest additional structural contributions.

The Right-Handed Parallel β-Helix Topology of Erwinia chrysanthemi Pectin Methylesterase Is Intimately Associated with Both Sequential Folding and Resistance to High Pressure

The complex topologies of large multi-domain globular proteins make the study of their folding and assembly particularly demanding. It is often characterized by complex kinetics and undesired side reactions, such as aggregation. The structural simplicity of tandem-repeat proteins, which are characterized by the repetition of a basic structural motif and are stabilized exclusively by sequentially localized contacts, has provided opportunities for dissecting their folding landscapes. In this study, we focus on the Erwinia chrysanthemi pectin methylesterase (342 residues), an all-β pectinolytic enzyme with a right-handed parallel β-helix structure. Chemicals and pressure were chosen as denaturants and a variety of optical techniques were used in conjunction with stopped-flow equipment to investigate the folding mechanism of the enzyme at 25 °C. Under equilibrium conditions, both chemical- and pressure-induced unfolding show two-state transitions, with average conformational stability (ΔG° = 35 ± 5 kJ·mol−1) but exceptionally high resistance to pressure (Pm = 800 ± 7 MPa). Stopped-flow kinetic experiments revealed a very rapid (τ < 1 ms) hydrophobic collapse accompanied by the formation of an extended secondary structure but did not reveal stable tertiary contacts. This is followed by three distinct cooperative phases and the significant population of two intermediate species. The kinetics followed by intrinsic fluorescence shows a lag phase, strongly indicating that these intermediates are productive species on a sequential folding pathway, for which we propose a plausible model. These combined data demonstrate that even a large repeat protein can fold in a highly cooperative manner.

Polymorphism of methyl 4-amino-3-phenylisothiazole-5-carboxylate: an experimental and theoretical study

Being a close analogue of amflutizole, methyl 4-amino-3-phenylisothiazole-5-carboxylate (C11H10N2O2S) was assumed to be capable of forming polymorphic structures. Noncentrosymmetric and centrosymmetric polymorphs have been obtained by crystallization from a series of more volatile solvents and from denser tetrachloromethane, respectively. Identical conformations of the molecule are found in both structures. The two polymorphs differ mainly in the intermolecular interactions formed by the amino group and in the type of stacking interactions between the π-systems. The most effective method for revealing packing motifs in structures with intermolecular interactions of different types (hydrogen bonding, stacking, dispersion, etc.) is to study the pairwise interaction energies using quantum chemical calculations. Molecules form a column as the primary basic structural motif due to stacking interactions in both polymorphic structures under study. The character of a column (straight or zigzag) is determined by the orientations of the stacked molecules (in a `head-to-head' or `head-to-tail' manner). Columns bound by intermolecular N-H...O and N-H...N hydrogen bonds form a double column as the main structural motif in the noncentrosymmetric structure. Double columns in the noncentrosymmetric structure and columns in the centrosymmetric structure interact strongly within the ab crystallographic plane, forming a layer as a secondary basic structural motif. The noncentrosymmetric structure has a lower density and a lower (by 0.59 kJ mol-1) lattice energy, calculated using periodic calculations, compared to the centrosymmetric structure.

Distorted Te nets in the modulated crystal structures of RETe1.94(1) (RE = La, Pr, Nd).

The two-dimensionally incommensurately modulated crystal structures of the compounds RETe1.94(1) (RE = La, Pr, Nd) were investigated by single-crystal X-ray diffraction. The compounds crystallize in the tetragonal superspace group P4/n(αβ½)00(-βα½)00 (No. 85.2.58.2) with q1 = αa*+βb*+½c* and q2 = -βa*+αb*+½c* and share a common motif of an alternating stacking of a puckered [RETe] layer and a planar [Te] layer. This basic structural motif is observed for all reported compounds with unusually large anisotropic displacement parameters in the planar [Te] layer. Taking the modulation into account, a distortion from this perfect square planar net is noted along with vacancies in the planar [Te] layer. The distortion leads to the formation of different discrete anions, like Te2-, Te22- and Te32-, similar to previously reported structures for REX2-δ compounds (RE = trivalent rare earth metal, X = S, Se, Te). The Te-Te distances in the modulated [Te] layer are found in a narrow range as compared to those in the corresponding sulfides and selenides.

Role of intermolecular interactions in formation of mono- and diaminopyridine crystals: study from the energetic viewpoint

The regularities of crystal structure organization in a series of mono- and diaminopyridines possessing biological activities were studied using an approach based on comparison of interaction energies between molecules calculated by ab initio quantum chemical method. The presence of the pyridine nitrogen atom causes the formation of N–H…Npyr hydrogen bond which is the strongest in all the studied structures. Being amphiphilic in hydrogen bond formation, the amino group possesses acceptor properties only in meta-position to the pyridine nitrogen atom in mono-aminopyridines. The presence of the two amino groups results in increasing of acceptor properties of both ones. The N–H…Nlp hydrogen bonds bind primary BSM (basic structural motif) in the structures of 2,5-diaminopyridine, 2,4-diaminopyridine and 3,4-diamonpyridine and form the primary BSM alongside with N–H…Npyr hydrogen bond in the structure of 2,3-diaminopyridine. The helical primary basic structural motif and double helical secondary basic structural motif in the 2,3-diaminopyridine crystal structure are very similar to the DNA helix and double helix.

Concomitant polymorphic forms of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole.

The dipharmacophore compound 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole, C10H11N5O, was studied on the assumption of its potential biological activity. Two concomitant polymorphs were obtained on crystallization from isopropanol solution and these were thoroughly studied. Identical conformations of the molecules are found in both structures despite the low difference in energy between the four possible conformers. The two polymorphs differ crucially with respect to their crystal structures. A centrosymmetric dimer formed due to both stacking interactions of the `head-to-tail' type and N-H...N(π) hydrogen bonds is the building unit in the triclinic structure. The dimeric building units form an isotropic packing. In the orthorhombic polymorphic structure, the molecules form stacking interactions of the `head-to-head' type, which results in their organization in a column as the primary basic structural motif. The formation of N-H...N(lone pair) hydrogen bonds between two neighbouring columns allows the formation of a double column as the main structural motif. The correct packing motifs in the two polymorphs could not be identified without calculations of the pairwise interaction energies. The triclinic structure has a higher density and a lower (by 0.60 kcal mol-1) lattice energy according to periodic calculations compared to the orthorhombic structure. This allows us to presume that the triclinic form of 3-cyclopropyl-5-(2-hydrazinylpyridin-3-yl)-1,2,4-oxadiazole is the more stable.

Synthesis, Single Crystal X-Ray Analysis, Prediction and Study of Pharmacological Activity of 4-(1H-Benzo[d]imidazol-2-yl)-1-Phenyl-1H-1,2,3-triazol-5-Amine and Its Solvates

A method for the synthesis of 4- (1H-benzo[d]imidazole-2-yl)-1-phenyl-1H-1,2,3-triazole-5-amine was developed, and the electronic and spatial structure of this molecule was studied theoretically and experimentally. The study of interaction energies between molecules by quantum-chemical calculations allows us to recognize different levels of crystal structure organization and describe the interaction types causing their formation. The classic N-H…N and C-H…N hydrogen bonds play the main role in all the studied crystals forming the primary basic structural motif. Their role is comparable with the role of the stacking interactions. The molecular docking study predicted that the studied compound may exhibit anti-hepatitis B activity, and experimental in vitro studies confirmed that it is a potent HBV inhibitor with IC50 in a low micromolar range.

Chiral Cocrystal Solid Solutions, Molecular Complexes, and Salts of N-Triphenylacetyl-l-Tyrosine and Diamines.

The molecular recognition process and the ability to form multicomponent supramolecular systems have been investigated for the amide of triphenylacetic acid and l-tyrosine (N-triphenylacetyl-l-tyrosine, TrCOTyr). The presence of several supramolecular synthons within the same amide molecule allows the formation of various multicomponent crystals, where TrCOTyr serves as a chiral host. Isostructural crystals of solvates with methanol and ethanol and a series of binary crystalline molecular complexes with selected organic diamines (1,5-naphthyridine, quinoxaline, 4,4′-bipyridyl, and DABCO) were obtained. The structures of the crystals were planned based on non-covalent interactions (O–H···N or N–H+···O− hydrogen bonds) present in a basic structural motif, which is a heterotrimeric building block consisting of two molecules of the host and one molecule of the guest. The complex of TrCOTyr with DABCO is an exception. The anionic dimers built off the TrCOTyr molecules form a supramolecular gutter, with trityl groups located on the edge and filled by DABCO cationic dimers. Whereas most of the racemic mixtures crystallize as racemic crystals or as conglomerates, the additional tests carried out for racemic N-triphenylacetyl-tyrosine (rac-TrCOTyr) showed that the compound crystallizes as a solid solution of enantiomers.

Influence of ortho-substituent on the molecular and crystal structures of 2-(N-arylimino)coumarin-3-carboxamide: isotypic and polymorphic structures.

During a comprehensive study of a series of 2-(N-arylimino)coumarin-3-carboxamides with the aryl group substituted in the ortho-position by either a halogen atom, a methyl group or a methoxy group, the existence of three groups of isotypic crystal structures has been revealed. The similarity of crystal structures belonging to the same groups was confirmed by the analysis based on the comparison of pairwise interactions energies obtained from quantum chemical calculations. Group I includes unsubstituted, methyl-substituted and polymorphic modification 1 of fluoro-substituted 2-(N-arylimino)coumarin-3-carboxamide. Structures of polymorphic modification 2 of fluoro-substituted derivative, chloro-substituted and polymorphic modification 1 of bromo-substituted 2-(N-arylimino)coumarin-3-carboxamide may represent group II. Group III contains structures of polymorphic modification 2 of bromo-substituted derivative, iodine- and methoxy-substituted 2-(N-arylimino)coumarin-3-carboxamides. Structures of the same type group have extremely close parameters of the unit cell as well as those of molecular and crystal structures. But they are not identical. Polymorphic modifications of fluoro- and bromo-substituted 2-(N-arylimino)coumarin-3-carboxamides belong to different crystal types mainly due to different arrangement of basic structural motifs separated out using quantum chemical calculations.

Three polymorphs of 3-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-1-benzopyran-2-one formed from different solvents.

The polymorphic study of 3-(3-phenyl-1H-1,2,4-triazol-5-yl)-2H-1-benzopyran-2-one, C17H11N3O2, was performed due to its potential biological activity and revealed three polymorphic modifications in the triclinic space group P-1, the monoclinic space group P21 and the orthorhombic space group Pbca. These polymorphs have a one-column layered type of crystal organization. The strongest interactions between the molecules of the studied structures is stacking between π-systems, while N-H...N and C-H...O hydrogen bonds link stacked columns forming layers as a secondary basic structural motif. C-H...π hydrogen bonds were observed between neighbouring layers and their role is the least significant in the formation of the crystal structure. Packing differences between the polymorphic modifications are minor and can be identified only using an analysis based on a comparison of the pairwise interaction energies.

Sub-nucleosomal Genome Structure Reveals Distinct Nucleosome Folding Motifs

Elucidating the global and local rules that govern genome-wide, hierarchical chromatin architecture remains a critical challenge. Current high-throughput chromosome conformation capture (Hi-C) technologies have identified large-scale chromatin structural motifs, such as topologically associating domains and looping. However, structural rules at the smallest or nucleosome scale remain poorly understood. Here, we coupled nucleosome-resolved Hi-C technology with simulated annealing-molecular dynamics (SA-MD) simulation to reveal 3D spatial distributions of nucleosomes and their genome-wide orientation in chromatin. Our method, called Hi-CO, revealed distinct nucleosome folding motifs across the yeast genome. Our results uncovered two types of basic secondary structural motifs in nucleosome folding: α-tetrahedron and β-rhombus analogous to α helix and β sheet motifs in protein folding. Using mutants and cell-cycle-synchronized cells, we further uncovered motifs with specific nucleosome positioning and orientation coupled to epigenetic features at individual loci. By illuminating molecular-level structure-function relationships in eukaryotic chromatin, our findings establish organizational principles of nucleosome folding.

Polymorphic modifications of a 1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide possessing strong diuretic properties.

6-Hydroxy-N-(4-methoxyphenyl)-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinoline-5-carboxamide, C19H16N2O4, possesses strong diuretic properties and can be used as a new hypertension remedy. Two polymorphic modifications of this compound have been found, namely the triclinic polymorph (space group P-1), with one molecule in the asymmetric unit, and the monoclinic polymorph (space group P21/n), with two molecules in asymmetric unit. An analysis of the pairwise interaction energies between the molecules in the crystal phase revealed differences in the crystal packing. The triclinic form has only one level of organization, namely a chain/column, while the monoclinic form has two levels of organization, with a chain/column as the primary basic structural motif and a layer as the secondary basic structural motif.

Virtual Prototyping and Parametric Design of 3D-Printed Tablets Based on the Solution of Inverse Problem.

The problem of designing tablet geometry and its internal structure that results into a specified release profile of the drug during dissolution was considered. A solution method based on parametric programming, inspired by CAD (computer-aided design) approaches currently used in other fields of engineering, was proposed and demonstrated. The solution of the forward problem using a parametric series of structural motifs was first carried out in order to generate a library of drug release profiles associated with each structural motif. The inverse problem was then solved in three steps: first, the combination of basic structural motifs whose superposition provides the closest approximation of the required drug release profile was found by a linear combination of pre-calculated release profiles. In the next step, the final tablet design was constructed and its dissolution curve found computationally. Finally, the proposed design was 3D printed and its dissolution profile was confirmed experimentally. The computational method was based on the numerical solution of drug diffusion in a boundary layer surrounding the tablet, coupled with erosion of the tablet structure encoded by the phase volume function. The tablets were 3D printed by fused deposition modelling (FDM) from filaments produced by hot-melt extrusion. It was found that the drug release profile could be effectively controlled by modifying the tablet porosity. Custom release profiles were obtained by combining multiple porosity regions in the same tablet. The computational method yielded accurate predictions of the drug release rate for both single- and multi-porosity tablets.