Aromatic Contacts Research Articles

Effect of Pressure on the Conformational Landscape of Human γD-Crystallin from Replica Exchange Molecular Dynamics Simulations.

Human γD-crystallin belongs to a crucial family of proteins known as crystallins located in the fiber cells of the human lens. Since crystallins do not undergo any turnover after birth, they need to possess remarkable thermodynamic stability. However, their sporadic misfolding and aggregation, triggered by environmental perturbations or genetic mutations, constitute the molecular basis of cataracts, which is the primary cause of blindness in the globe according to the World Health Organization. Here, we investigate the impact of high pressure on the conformational landscape of wild-type HγD-crystallin using replica exchange molecular dynamics simulations augmented with principal component analysis. We find pressure to have a modest impact on global measures of protein stability, such as root-mean-square displacement and radius of gyration. Upon projecting our trajectories along the first two principal components from principal component analysis, however, we observe the emergence of distinct free energy basins at high pressures. By screening local order parameters previously shown or hypothesized as markers of HγD-crystallin stability, we establish correlations between a tyrosine-tyrosine aromatic contact within the N-terminal domain and the protein's end-to-end distance with projections along the first and second principal components, respectively. Furthermore, we observe the simultaneous contraction of the hydrophobic core and its intrusion by water molecules. This exploration sheds light on the intricate responses of HγD-crystallin to elevated pressures, offering insights into potential mechanisms underlying its stability and susceptibility to environmental perturbations, crucial for understanding cataract formation.

Engineered π⋯π interactions favour supramolecular dimers X@[FeL3]2 (X = Cl, Br, I): solid state and solution structure.

Ditopic bis-pyrazolylpyridine ligands usually react with divalent metal ions (M2+) to produce dinuclear triple-stranded helicates [M2L3]4+ or, via π⋯π interactions, dimers of monoatomic complexes ([ML3]2)4+. The introduction of an additional benzene ring at each end of ligand L increases the number of aromatic contacts within the supramolecular aggregate by 40%, driving the self-recognition process in an irreversible manner. Consequently, the mixing of new bis-pyrazolylquinoline L2 with FeX2 salts leads to crystallization of the tripartite high-spin assemblies (X@[Fe(L2)3]2)3+ (X = Cl, Br or I). The aggregates exhibit exceptional stability, as confirmed by a combination of paramagnetic 1H NMR techniques, demonstrating their persistence in solution. Our investigations further reveal that the guests Br- and I- are retained inside the associate in solution but Cl- is immediately released, resulting in the formation of the empty supramolecular dimer ([Fe(L2)3]2)4+.

Kinetic study on the adsorption of some polycyclic aromatic hydrocarbons using dinitrodiphenyldiquinoline adsorbent

In this study, a dinitrodiphenyldiquinoline derivative is synthesized, purified, and characterized, and its adsorptive ability is examined for the first time. Twelve common polycyclic aromatic hydrocarbons are chosen as potential adsorbates for removal by using dinitrodiphenyldiquinoline as an adsorbent surface. The adsorptive capacity and the efficiency of removal depend on several variables such as adsorbent dose, polycyclic aromatic hydrocarbon initial concentration, pH, and contact time. This paper summarizes the adsorbent parameters and the kinetic models that can optimize and describe the adsorption process used to treat aqueous solutions of polycyclic aromatic hydrocarbons. Experimentally, the optimum adsorbent dose, the initial concentration, and contact time are found to be 0.1 g, 1 ppm, and 60 min, respectively. Mathematical treatment of the adsorption data reveals that the adsorption of all the polycyclic aromatic hydrocarbons by dinitrodiphenyldiquinoline adopted a pseudo second-order adsorption model. As a result, the dinitrodiphenyldiquinoline derivative is found to be a very good adsorbent surface for several hazardous organic pollutants such as polycyclic aromatic hydrocarbons.

Unraveling the impact of hydrogen bonding and C‒H…π(CN) interactions in crystal engineering of cyclic aminobenzonitriles: A combined X-ray crystallographic and computational investigation

The essential role of organic crystals in drug development represents a significant research area and remains enduringly topical within the pharmaceutical industry. In the present study, four cyclic aminobenzonitriles 3a-d were prepared through the nucleophilic aromatic substitution reaction of 4-fluorobenzonitrile with various cyclic amines. The synthesized compounds were obtained in moderate to good yields and structurally characterized by FTIR, NMR spectroscopy, mass spectrometry and X-ray crystallography. The crystal packing of these compounds predominantly involves the use of hydrogen bonding interactions (C-H…N, C-H…S, C-H…O) and aromatic contacts (C-H…π(ring & CN), π…π) to govern the complex structural topology. These noncovalent interactions were further evaluated by molecular electrostatic potential (MEP) surface analysis and DFT energy calculations confirming the importance of π-stacking and CH…π interactions, either involving the arene or the π-system of the cyano groups. These interactions have been further characterized using the QTAIM/NCIplot computational tool.

Supramolecular arrangements in the crystal structures and interaction energy calculations of resonance-assisted hydrogen-bridged (RAHB) rings – RAHB/RAHB and RAHB/C6 aromatic contacts

Supramolecular arrangements in the crystal structures and interaction energy calculations of resonance-assisted hydrogen-bridged (RAHB) rings – RAHB/RAHB and RAHB/C₆ aromatic contacts

Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs.

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp1033.32, TAAR1; Asp1163.32, 5HT1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.

Prebiotic Peptides Based on the Glycocodon Theory Analyzed with FRET.

In modern protein–carbohydrate interactions, carbohydrate–aromatic contact with CH–π interactions are used. Currently, they are considered driving forces of this complexation. In these contacts, tryptophan, tyrosine, and histidine are preferred. In this study, we focus on primary prebiotic chemistry when only glycine, alanine, aspartic acid, and valine are available in polypeptides. In this situation, when the aromatic acids are not available, hydrogen-bonding aspartic acid must be used for monosaccharide complexation. It is shown here that (DAA)n polypeptides play important roles in primary “protein”–glucose recognition, that (DGG)n plays an important role in “protein”–ribose recognition, and that (DGA)n plays an important role in “protein”–galactose recognition. Glucose oxidase from Aspergillus niger, which still has some ancient prebiotic sequences, is chosen here as an example for discussion.

Spin-Crossover 2-D Hofmann Frameworks Incorporating an Amide-Functionalized Ligand: N-(pyridin-4-yl)benzamide

Two analogous 2-D Hofmann-type frameworks, which incorporate the novel ligand N-(pyridin-4-yl)benzamide (benpy) [FeII(benpy)2M(CN)4]·2H2O (M = Pd (Pd(benpy)) and Pt (Pt(benpy))) are reported. The benpy ligand was explored to facilitate spin-crossover (SCO) cooperativity via amide group hydrogen bonding. Structural analyses of the 2-D Hofmann frameworks revealed benpy-guest hydrogen bonding and benpy-benpy aromatic contacts. Both analogues exhibited single-step hysteretic spin-crossover (SCO) transitions, with the metal-cyanide linker (M = Pd or Pt) impacting the SCO spin-state transition temperature and hysteresis loop width (Pd(benpy): T½↓↑: 201, 218 K, ∆T: 17 K and Pt(benpy): T½↓↑: 206, 226 K, ∆T: 20 K). The parallel structural and SCO changes over the high-spin to low-spin transition were investigated using variable-temperature, single-crystal, and powder X-ray diffraction, Raman spectroscopy, and differential scanning calorimetry. These studies indicated that the ligand–guest interactions facilitated by the amide group acted to support the cooperative spin-state transitions displayed by these two Hofmann-type frameworks, providing further insight into cooperativity and structure–property relationships.

σ-Hole interactions in small-molecule compounds containing divalent sulfur groups R1-S-R2.

Hydrogen bonds, aromatic stacking contacts and σ-hole interactions are all noncovalent interactions commonly observed in biological systems. Structural data derived from the Protein Data Bank showed that methionine residues can interact with oxygen atoms through directional S...O contacts in the protein core. In the present work, the Cambridge Structural Database (CSD) was used in conjunction with ab initio calculations to explore the σ-hole interaction properties of small-molecule compounds containing divalent sulfur. CSD surveys showed that 7095 structures contained R1-S-R2 groups that interact with electronegative atoms like N, O, S and Cl. Frequencies of occurrence and geometries of the interaction were dependent on the nature of R1 and R2, and the hybridization of carbon atoms in C,C-S, and C,S-S fragments. The most common interactions in terms of frequency of occurrence were C,C-S...O, C,C-S...N and C,C-S...S with predominance of Csp2. The strength of the chalcogen interaction increased when enhancing the electron-withdrawing character of the substituents. The most positive electrostatic potentials (VS,max; illustrating positive σ-holes) calculated on R1-S-R2 groups were located on the S atom, in the S-R1 and S-R2 extensions, and increased with electron-withdrawing R1 and R2 substituents like the interaction strength did. As with geometric data derived from the CSD, interaction geometries calculated for some model systems and representative CSD compounds suggested that the interactions were directed in the extensions of S-R1 and S-R2 bonds. The values of complexation energies supported attractive interactions between σ-hole bond donors and acceptors, enhanced by dispersion. The interactions of R1-S-R2 with large VS,max and nucleophiles with large negative VS,min coherently provided more negative energies. According to NBO analysis, chalcogen interactions consisted of charge transfer from a nucleophile lone pair to an S-R1 or S-R2 antibonding orbital. The directional σ-hole interactions at R1-S-R2 can be useful in crystal engineering and the area of supramolecular biochemistry.

X-Ray Structure, DFT Study of p-Chlorobenzoic Acid, and the Effect of In Silico Molecular Docking on Tankyrase I Enzyme

p-Chlorbenzoic acid carries a 4-chloro position atom where it may be important in coordinated with and control certain biological parameters , it can inhibit the action of specific enzyme in organisms. X‑ray data collection gives information about the analysis of the covalent and the non-covalent interactions in 3D quantitatively. Recrystallization of p-chlorobenzoic acid was carried out to remove any impurities and to be prepared in pure crystal form. X-ray analytical technique studied the structure and geometrical parameters. The experimental data were compared with the calculated ones for the optimized structure obtained from density functional theory (DFT) studies. X-ray structure of p-chlorobenzoic acid is found in dimer form stabilized with intermolecular H-bond interaction. Infrared spectra and thermal analysis of this compound were studied. DFT calculations were carried out and structural geometrical parameters were evaluated. In-silico molecular docking of tested ligand in Tankyrase I enzyme shows a number of hydrogen bond interactions, chlorine and aromatic ring interaction and polar contact, these predicted interactions can inhibit the active sites of amino acids of Tankyrase I enzyme, so this inhibition can control some biological activities especially anticancer effect.

An amyloidogenic hexapeptide from the cataract-associated γD-crystallin is a model for the full-length protein and is inhibited by naphthoquinone-tryptophan hybrids

The eye lens is rich in proteins called crystallins, whose native conformation is crucial for preserving its transparency. With aging, crystallins may be exposed to environmental changes, which could lead to their aggregation and eventually to cataract development. Human γD-crystallin, among the most abundantly expressed γ-crystallins in the lens, was shown to form amyloid aggregates under denaturing conditions in vitro. However, the exact mechanism of aggregation remains to be clearly defined. Here, using prediction algorithms and biophysical methods, we identified a hexapeptide 41GCWMLY46 as a most aggregative fragment in human γD-crystallin. Two aromatic naphthoquinone-tryptophan hybrid molecules (NQTrp and Cl-NQTrp), inhibited the in vitro aggregation of this hexapeptide as well as full-length γD-crystallin in a dose-dependent manner, plausibly facilitated by hydrogen bonding and aromatic contacts with the hydrophobic residues. The two compounds had no toxic effect toward retinal cell culture and reduced the cytotoxicity induced by aggregates of the hexapeptide. In addition, NQTrp and Cl-NQTrp were able to disassemble pre-formed aggregates of the hexapeptide and the full-length γD-crystallin. Our results indicate that the amyloidogenic hexapeptide is a useful model for screening inhibitors of γD-crystallin and that the NQTrp hybrid scaffolds may serve as leads for developing new drugs for treating cataract.

Slow ring flips in aromatic cluster of GB1 studied by aromatic 13C relaxation dispersion methods

Ring flips of phenylalanine and tyrosine are a hallmark of protein dynamics. They report on transient breathing motions of proteins. In addition, flip rates also depend on stabilizing interactions in the ground state, like aromatic stacking or cation–π interaction. So far, experimental studies of ring flips have almost exclusively been performed on aromatic rings without stabilizing interactions. Here we investigate ring flip dynamics of Phe and Tyr in the aromatic cluster in GB1. We found that all four residues of the cluster, Y3, F30, Y45 and F52, display slow ring flips. Interestingly, F52, the central residue of the cluster, which makes aromatic contacts with all three others, is flipping significantly faster, while the other rings are flipping with the same rates within margin of error. Determined activation enthalpies and activation volumes of these processes are in the same range of other reported ring flips of single aromatic rings. There is no correlation of the number of aromatic stacking interactions to the activation enthalpy, and no correlation of the ring’s extent of burying to the activation volume. Because of these findings, we speculate that F52 is undergoing concerted ring flips with each of the other rings.

DeepDrug3D: Classification of ligand-binding pockets in proteins with a convolutional neural network.

Comprehensive characterization of ligand-binding sites is invaluable to infer molecular functions of hypothetical proteins, trace evolutionary relationships between proteins, engineer enzymes to achieve a desired substrate specificity, and develop drugs with improved selectivity profiles. These research efforts pose significant challenges owing to the fact that similar pockets are commonly observed across different folds, leading to the high degree of promiscuity of ligand-protein interactions at the system-level. On that account, novel algorithms to accurately classify binding sites are needed. Deep learning is attracting a significant attention due to its successful applications in a wide range of disciplines. In this communication, we present DeepDrug3D, a new approach to characterize and classify binding pockets in proteins with deep learning. It employs a state-of-the-art convolutional neural network in which biomolecular structures are represented as voxels assigned interaction energy-based attributes. The current implementation of DeepDrug3D, trained to detect and classify nucleotide- and heme-binding sites, not only achieves a high accuracy of 95%, but also has the ability to generalize to unseen data as demonstrated for steroid-binding proteins and peptidase enzymes. Interestingly, the analysis of strongly discriminative regions of binding pockets reveals that this high classification accuracy arises from learning the patterns of specific molecular interactions, such as hydrogen bonds, aromatic and hydrophobic contacts. DeepDrug3D is available as an open-source program at https://github.com/pulimeng/DeepDrug3D with the accompanying TOUGH-C1 benchmarking dataset accessible from https://osf.io/enz69/.

Crystal and Electron Properties of Carbamazepine–Aspirin Co-crystal

Carbamazepine (CBZ) and aspirin (ASP) drug molecules in their 1:1 cocrystal interact by relatively strong hydrogen bonds and aromatic–aromatic contacts. The crystal structure and the experimental electron density in the CBZ:ASP cocrystal were derived from a high resolution X-ray diffraction experiment at 100 K, and the results are compared to those previously obtained for the CBZ form III. The isobaric thermal expansion tensor appears to be much more anisotropic for the cocrystal than for CBZ form III. The thermal expansion coefficients αV are found equal to 1.3 for CBZ III and 1.5 × 10–4 K–1 for the CBZ:ASP cocrystal. The interactions in the CBZ:ASP cocrystal have also been analyzed through the electrostatic properties derived from both experimental and theoretical electron densities: topological features, atomic charges, and electrostatic potential. A very good agreement was found for the values of the electron density at the critical points ρ(rCP) obtained from both experiment and theory. This is not, ...

Intramolecular Nitro-Aromatic Interactions Within a Molecular Torsion Balance: A Quantitative Assessment

Interactions between a nitro group and an aromatic ring have been identified as an important aspect within the solid-state structures of many energetic materials. We investigated nitro-aromatic interactions within a molecular “torsion balance”, both in solid-state as well as in solution. Our balance features a Troger’s base and a nitroalkene functionality substituted at 1 and 8 positions of a naphthalene ring. Because of restricted rotation around a biaryl axis, the balance can adapt two principal atropisomeric conformations: folded and unfolded. Intramolecular nitro-aromatic interactions are feasible only in the folded state. A torsion balance containing a highly electron deficient aromatic ring crystallized in the folded state leading to the formation of a short (<3.4 A) intramolecular NO···aromatic contact. On the other hand, with an electron rich aromatic, the balance crystallized in the unfolded conformation in which the nitro group avoids the aromatic surface. In solution, the strength of the intera...

Structure of the mouse TRPC4 ion channel

Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Here we report a cryo-electron microscopy (cryo-EM) structure of TRPC4 in its unliganded (apo) state to an overall resolution of 3.3 Å. The structure reveals a unique architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique cytosolic domain. This unique cytosolic N-terminal domain forms extensive aromatic contacts with the TRP and the C-terminal domains. The comparison of our structure with other known TRP structures provides molecular insights into TRPC4 ion selectivity and extends our knowledge of the diversity and evolution of the TRP channels.

Spectra and Simulation of Model Beta-Sheets and Hairpins. Impact of Turn Sequences and Aromatic Contacts on Equilibria and Dynamics

β-sheets can be modeled as antiparallel strands coupled by turns. Isolated model systems are less stable, due to amide solvation), but can be induced to fold into sheet-like structures by restricting the conformational space of turn residues, such as with DPro-Gly sequences, or by inclusion of cross-strand hydrophobic interactions, especially aromatic contacts, which tend to desolvate parts of the structure. Expanding to multistrand structures can provide different characteristics for study of physical properties. Larger structures have strand differentiation, since the center strand of a three-strand sheet has a different H-bonds than the outer ones. In larger structures, integral hairpin-like sequences of either the first two or the second two strands might have different stabilities and folding mechanisms, if it is overall a multistate process. To explore these factors, we have prepared a series of three-stranded sheet structures that are stabilized by either DPro-Gly or by Aib-Gly turns and contain various Trp-Tyr side-chain contacts. To assess the impact of the third strand we also separately synthesized the component hairpins and studied their relative properties with temperature dependent circular dichroism, fluorescence, infrared (IR) and vibrational circular dichroism for evaluation of global thermodynamic equilibria as well as IR–detected temperature jump relaxation dynamics of selected components (strands, turns). Where possible, NMR structures were obtained for comparison and MD simulations of unfolding were used to aid interpretations. While all the sequences showed evidence of β-structure formation, the extent and stability varied markedly. In terms of equilibrium properties, the turn residues (especially DPro-Gly) seemed to have the strongest influence, while the aromatic contacts had minor effects. However in terms of dynamics, the aromatic effects differentiated the structures more, suggesting a variation in the folding mechanisms.

Role of Aromatic Cross-Links in Structure and Dynamics of Model Three-Stranded β-Sheet Peptides.

A series of closely related peptide sequences that form triple-strand structures was designed with a variation of cross-strand aromatic interactions and spectroscopically studied as models for β-sheet formation and stabilities. Structures of the three-strand models were determined with NMR methods and temperature-dependent equilibrium studies performed using circular dichroism and Fourier transform infrared spectroscopies. Our equilibrium data show that the presence of a direct cross-strand aromatic contact in an otherwise folded peptide does not automatically result in an increased thermal stability and can even distort the structure. The effect on the conformational dynamics was studied with infrared-detected temperature-jump relaxation methods and revealed a high sensitivity to the presence and the location of the aromatic cross-links. Aromatic contacts in the three-stranded peptides slow down the dynamics in a site-specific manner, and the impact seems to be related to the distance from the turn. With a Xxx-DPro linkage as a probe with some sensitivity for the turn, small differences were revealed in the relative relaxation of the sheet strands and turn regions. In addition, we analyzed the component hairpins, which showed less uniform dynamics as compared to the parent three-stranded β-sheet peptides.

Structural Basis for the Influence of A1, 5A, and W51W57 Mutations on the Conductivity of the Geobacter sulfurreducens Pili

The metallic-like conductivity of the Geobacter sulfurreducens pilus and higher conductivity of its mutants reflected that biological synthesis can be utilized to improve the properties of electrically conductive pili. However, the structural basis for diverse conductivities of nanowires remains uncertain. Here, the impacts of point mutations on the flexibility and stability of pilins were investigated based on molecular dynamics simulations. Structures of the G. sulfurreducens pilus and its mutants were constructed by Rosetta. Details of the structure (i.e., electrostatic properties, helical parameters, residue interaction network, distances between amino acids, and salt bridges) were analyzed by PDB2PQR, Rosetta, RING, PyMOL, and VMD, respectively. Changes in stability, flexibility, residue interaction, and electrostatic properties of subunits directly caused wild-type pilin and its mutants assemble different structures of G. sulfurreducens pili. By comparing the structures of pili with different conductivities, the mechanism by which the G. sulfurreducens pilus transfers electron along pili was attributed, at least in part, to the density of aromatic rings, the distances between neighboring aromatic rings, and the local electrostatic environment around aromatic contacts. These results provide new insight into the potential for the biological synthesis of highly electrically conductive, nontoxic nanowires.

Aromatic interactions at the ligand-protein interface: Implications for the development of docking scoring functions.

The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand-protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand-protein complexes, considering various combinations of aromatic amino acid residues and ligand rings. The geometry of interfacial π-π stacking in crystal structures accords with experimental and theoretical data collected for simple systems, such as the benzene dimer. Many contemporary ligand docking programs implicitly treat aromatic stacking with van der Waals and Coulombic potentials. Although this approach generally provides a sufficient specificity to model aromatic interactions, the geometry of π-π contacts in high-scoring docking conformations could still be improved. The comprehensive analysis of aromatic geometries at ligand-protein interfaces lies the foundation for the development of type-specific statistical potentials to more accurately describe aromatic interactions in molecular docking. A Perl script to detect and calculate the geometric parameters of aromatic interactions in ligand-protein complexes is available at https://github.com/michal-brylinski/earomatic. The dataset comprising experimental complex structures and computer-generated models is available at https://osf.io/rztha/.