Aromatic Stacking Interactions Research Articles

Determinants of Unfolding Cooperativity and Binding Are Decoupled in a DNA Binding Domain.

The relative magnitudes of noncovalent stabilization energies or the coupling free energies in folded proteins are anisotropically distributed, uniquely influencing folding and functional behaviors. In this regard, the fructose repressor (FruR) DBD belonging to the LacR repressor family harbors a three-residue insertion─KQY─between the canonical second and third helices. This sequence insertion promotes a strong Tyr-Tyr stacking interaction that is not observed in related homologues. Combining experiments with simulations, we show that the Tyr-Tyr stacking contributes to a decoupled unfolding due to the localization of a large part of the stabilization energy in this specific structural region. This leads to melting temperatures from different probes spanning nearly 10 K, while concomitantly stabilizing a partially structured intermediate state. Disruption of the aromatic stacking interaction via an alanine mutation promotes a molten-globular state whose native ensemble is replete with non-native interactions while displaying enhanced thermodynamic fluctuations and minimal calorimetric cooperativity. Surprisingly, the molten-globular variant of FruR DBD binds to the operator site on DNA with an affinity similar to that of the wild-type but with altered secondary-structure characteristics in the bound state, underscoring the chaperone-like role of DNA through its large negative electrostatic potential. FruR DBD thus appears to be at the verge of disorder as expected of an entropically destabilizing three-residue insertion but is rescued by the aromatic stacking interaction that distinctly dictates the finer details of stability, cooperativity, and binding.

Nanocomposites of thermoplastic matrices with non-covalent fullerene reinforcement—Structural diversity, physical impact and potential

Fullerene has been acknowledged as a significant nanocarbon nanofiller enhancing the imperative polymer characteristics. Since, thermoplastic polymers constitute a large group of polymeric materials, fullerene has been used as reinforcement in these matrices mostly via non-covalent means. This state-of-the-art review article summarizes thermoplastic polymer nanocomposites reinforced with fullerene nano-additives without involving any covalent interactions. Accordingly, thermoplastic polymer/fullerene nanocomposites of interest have non-covalent or physical interactions in the matrix-nanofiller such as van der Waals forces, electrostatic interactions, hydrogen bonding, and aromatic stacking interactions. Number of thermoplastic polymers including polyamide, polyurethanes, and block copolymers have been non-covalently or physically reinforced with the fullerene molecules. Ensuing high performance thermoplastic polymer/fullerene nanocomposites exhibited improved microstructure, electrical, mechanical, thermal, and other physical properties. Enhancements in the thermal, mechanical, and electrical properties of the thermoplastic/fullerene nanomaterials were found dependent upon the nanofiller contents, orientations, interfacial effects, and processing. Consequently, the polyamide/fullerene systems were found efficient to enhance the glass transition up to 260°C, in addition to optimum mechanical properties. Polyurethane/fullerene systems performed better for improved tensile strength and young’s modulus features up to 90 MPa and 48 GPa, respectively. System based on poly (methyl methacrylate) and fullerene has resulted in high thermal degradation temperature in the range of 501-633°C with fine electrical conductivity of 1.3 Scm−1. Using combination of fullerene and graphene nanofiller (due to synergistic effects) has been found to improve the electrical conductivity considerably in the range of 1.8–2.5 Scm−1 for a polystyrene and block copolymer system. However, attaining fine fullerene nanoparticle dispersion of non-covalently reinforced matrices have been found important affecting the final nanocomposite properties. Consequently, processability and essential characteristics of non-covalently fullerene filled nanocomposites can be influenced due to nanoparticle aggregation. Hence, the physical property enhancement potential of physical linking between the non-covalently linked thermoplastics-fullerene has been portrayed in this article. Research on non-covalently interacted thermoplastic polymer/fullerene nanocomposites revealed technical potential ranging from energy/electronic devices to engineering and biomedical sectors. This review article can be a useful guide for the field researchers towards the development of advanced systems using non-covalently linked polymer/fullerene nanomaterials for future technical applications.

Five similar anthocyanidin molecules display distinct disruptive effects and mechanisms of action on Aβ1–42 protofibril: A molecular dynamic simulation study

Alzheimer's disease (AD) is associated with the deposition of amyloid-β (Aβ) fibrillary aggregates. Disaggregation of Aβ fibrils is considered as one of the promising AD treatments. Recent experimental studies showed that anthocyanidins, one type of flavonoids abundant in fruits/vegetables, can disaggregate Aβ fibrillary aggregates. However, their relative disruptive capacities and underlying mechanisms are largely unknown. Herein, we investigated the detailed interactions between five most common anthocyanidins (cyanidin, aurantinidin, peonidin, delphinidin, and pelargonidin) and Aβ protofibril (an intermediate of Aβ fibrillization) by performing microsecond molecular dynamic simulations. We found that all five anthocyanidins can destroy F4-L34-V36 hydrophobic core and K28-A42 salt bridge, leading to Aβ protofibril destabilization. Aurantinidin exhibits the strongest damage to Aβ protofibril (with the most severe disruption on K28-A42 salt bridges), followed by cyanidin (with the most destructive effect on F4-L34-V36 core). Detailed analyses reveal that the protofibril-destruction capacities of anthocyanidins are subtly modulated by the interplay of anthocyanidin-protofibril hydrogen bonding, hydrophobic, aromatic stacking interactions, which are dictated by the number or location of hydroxyl/methyl groups of anthocyanidins. These findings provide important mechanistic insights into Aβ protofibril disaggregation by anthocyanidins, and suggest that aurantinidin/cyanidin may serve as promising starting-points for the development of new drug candidates against AD.

The molecular basis of dapsone activation of CYP2C9-catalyzed nonsteroidal anti-inflammatory drug oxidation

Positive heterotropic cooperativity, or "activation," results in an instantaneous increase in enzyme activity in the absence of an increase in protein expression. Thus, cytochrome P450 (CYP) enzyme activation presents as a potential drug-drug interaction mechanism. It has been demonstrated previously that dapsone activates the CYP2C9-catalyzed oxidation of a number of nonsteroidal anti-inflammatory drugs invitro. Here, we conducted molecular dynamics simulations (MDS) together with enzyme kinetic investigations and site-directed mutagenesis to elucidate the molecular basis of the activation of CYP2C9-catalyzed S-flurbiprofen 4'-hydroxylation and S-naproxen O-demethylation by dapsone. Supplementation of incubations of recombinant CYP2C9 with dapsone increased the catalytic efficiency of flurbiprofen and naproxen oxidation by 2.3- and 16.5-fold, respectively. MDS demonstrated that activation arises predominantly from aromatic interactions between the substrate, dapsone, and the phenyl rings of Phe114 and Phe476 within a common binding domain of the CYP2C9 active site, rather than involvement of a distinct effector site. Mutagenesis of Phe114 and Phe476 abrogated flurbiprofen and naproxen oxidation, and MDS and kinetic studies with the CYP2C9 mutants further identified a pivotal role of Phe476 in dapsone activation. MDS additionally showed that aromatic stacking interactions between two molecules of naproxen are necessary for binding in a catalytically favorable orientation. In contrast to flurbiprofen and naproxen, dapsone did not activate the 4'-hydroxylation of diclofenac, suggesting that the CYP2C9 active site favors cooperative binding of nonsteroidal anti-inflammatory drugs with a planar or near-planar geometry. More generally, the work confirms the utility of MDS for investigating ligand binding in CYP enzymes.

Significance of Five-Membered Heterocycles in Human Histone Deacetylase Inhibitors.

Five-membered heteroaromatic rings, in particular, have gained prominence in medicinal chemistry as they offer enhanced metabolic stability, solubility and bioavailability, crucial factors in developing effective drugs. The unique physicochemical properties and biological effects of five-membered heterocycles have positioned them as key structural motifs in numerous clinically effective drugs. Hence, the exploration of five-ring heterocycles remains an important research area in medicinal chemistry, with the aim of discovering new therapeutic agents for various diseases. This review addresses the incorporation of heteroatoms such as nitrogen, oxygen and sulfur into the aromatic ring of these heterocyclic compounds, enhancing their polarity and facilitating both aromatic stacking interactions and the formation of hydrogen bonds. Histone deacetylases are present in numerous multiprotein complexes within the epigenetic machinery and play a central role in various cellular processes. They have emerged as important targets for cancer, neurodegenerative diseases and other therapeutic indications. In histone deacetylase inhibitors (HDACi's), five-ring heterocycles perform various functions as a zinc-binding group, a linker or head group, contributing to binding activity and selective recognition. This review focuses on providing an up-to-date overview of the different five-membered heterocycles utilized in HDACi motifs, highlighting their biological properties. It summarizes relevant publications from the past decade, offering insights into the recent advancements in this field of research.

Mutagenesis and structural studies reveal the basis for the specific binding of SARS-CoV-2 SL3 RNA element with human TIA1 protein

Viral RNA-host protein interactions are indispensable during RNA virus transcription and replication, but their detailed structural and dynamical features remain largely elusive. Here, we characterize the binding interface for the SARS-CoV-2 stem-loop 3 (SL3) cis-acting element to human TIA1 protein with a combined theoretical and experimental approaches. The highly structured SARS-CoV-2 SL3 has a high binding affinity to TIA1 protein, in which the aromatic stacking, hydrogen bonds, and hydrophobic interactions collectively direct this specific binding. Further mutagenesis studies validate our proposed 3D binding model and reveal two SL3 variants have enhanced binding affinities to TIA1. And disruptions of the identified RNA-protein interactions with designed antisense oligonucleotides dramatically reduce SARS-CoV-2 infection in cells. Finally, TIA1 protein could interact with conserved SL3 RNA elements within other betacoronavirus lineages. These findings open an avenue to explore the viral RNA-host protein interactions and provide a pioneering structural basis for RNA-targeting antiviral drug design.

PET-RAFT Polymerization of Star Polymers with Folded ortho-Phenylene Cores.

ortho-Phenylenes are one of simplest classes of aromatic foldamers, adopting helical geometries because of aromatic stacking interactions. The folding and misfolding of ortho-phenylenes are slow on the NMR timescale at or below room temperature, allowing detection of folding states using 1 H NMR spectroscopy. Here, an ortho-phenylene hexamer was coupled with a RAFT chain transfer agent (CTA) on each repeat unit. A variety of acrylic monomers were polymerized onto the CTA-functionalized ortho-phenylene using PET-RAFT to yield functionalized star polymers with ortho-phenylene cores. The steric bulk of the acrylate monomer units as well as the chain length of each arm of the star polymer was varied. 1 H NMR spectroscopy showed that the folding of the ortho-phenylenes did not vary, providing a robust helical core for star polymer systems. This article is protected by copyright. All rights reserved.

Dissecting how ALS-associated D290V mutation enhances pathogenic aggregation of hnRNPA2286–291 peptides: Dynamics and conformational ensembles

The aggregation of RNA binding proteins, including hnRNPA1/2, TDP-43 and FUS, is heavily implicated in causing or increasing disease risk for a series of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). A recent experimental study demonstrated that an ALS-related D290V mutation in the low complexity domain (LCD) of hnRNPA2 can enhance the aggregation propensity of wild type (WT) hnRNPA2286–291 peptide. However, the underlying molecular mechanisms remain elusive. Herein, we investigated effects of D290V mutation on aggregation dynamics of hnRNPA2286–291 peptide and the conformational ensemble of hnRNPA2286–291 oligomers by performing all-atom molecular dynamic and replica-exchange molecular dynamic simulations. Our simulations demonstrate that D290V mutation greatly reduces the dynamics of hnRNPA2286–291 peptide and that D290V oligomers possess higher compactness and β-sheet content than WT, indicative of mutation-enhanced aggregation capability. Specifically, D290V mutation strengthens inter-peptide hydrophobic, main-chain hydrogen bonding and side-chain aromatic stacking interactions. Those interactions collectively lead to the enhancement of aggregation capability of hnRNPA2286–291 peptides. Overall, our study provides insights into the dynamics and thermodynamic mechanisms underlying D290V-induced disease-causing aggregation of hnRNPA2286–291, which could contribute to better understanding of the transitions from reversible condensates to irreversible pathogenic aggregates of hnRNPA2 LCD in ALS-related diseases.

The salicylate 1,2-dioxygenase from Pseudaminobacter salicylatoxidans DSM 6986T is a bifunctional enzyme that inactivates the mycotoxin ochratoxin A by a novel amidohydrolase activity

The salicylate 1,2-dioxygenase from the bacterium Pseudaminobacter salicylatoxidans DSM 6986T (PsSDO) is a versatile metalloenzyme that participates in the aerobic biodegradation of aromatic compounds, such as gentisates and salicylates. Surprisingly, and unrelated to this metabolic role, it has been reported that PsSDO may transform the mycotoxin ochratoxin A (OTA), a molecule that appears in numerous food products that results in serious biotechnological concern. In this work, we show that PsSDO, together with its dioxygenase activity, behaves as an amidohydrolase with a marked specificity for substrates containing a C-terminal phenylalanine residue, similar to OTA, although its presence is not an absolute requirement. This side chain would establish aromatic stacking interactions with the indole ring of Trp104. PsSDO hydrolysed the amide bond of OTA rendering the much less toxic ochratoxin α and L-β-phenylalanine. The binding mode of OTA and of a diverse set of synthetic carboxypeptidase substrates these substrates have been characterized by molecular docking simulations, which has permitted us to propose a catalytic mechanism of hydrolysis by PsSDO that, similarly to metallocarboxypeptidases, assumes a water-induced pathway following a general acid/base mechanism in which the side chain of Glu82 would provide the solvent nucleophilicity required for the enzymatic reaction. Since the PsSDO chromosomal region, absent in other Pseudaminobacter strains, contained a set of genes present in conjugative plasmids, it could have been acquired by horizontal gene transfer, probably from a Celeribacter strain.

Static Binding and Dynamic Transporting-Based Design of Specific Ring-Chain-Ring Acetylcholinesterase Inhibitor: From Galantamine to Natural Product.

Acetylcholinesterase (AChE) is a key target for the current symptomatic treatment of Alzheimer's disease, and galantamine is a clinical anticholinesterase drug with transiently acting characteristic and good selectivity for AChE. The present theoretical-experimental work improves the drug's residence time without reducing the inhibition effect, thus providing a crucial breakthrough for modifying the inhibitor of AChE with better kinetic behavior. The static binding and dynamic delivery properties acquired from atomic view reveal that the galantamine simply occupies a catalytic anionic site, and its release from AChE needs only ∼8.6 kcal/mol. Both of these may cause the short residence time of galantamine. The hotspots and most favorable transport mechanism are identified, and the hydrogen bond and aromatic stacking interactions are observed to play crucial roles for galantamine binding and release in AChE. The typical peripheral anionic site arisen at the delivery process would provide another key occupation to enhance the anti-release ability for inhibitors. The compound with "specific-ring-chain-ring" framework with detailed beneficial modification scheme is summarized, which may improve the residence time of the inhibitor in AChE. The thermodynamic and dynamic properties of galantamine derivatives are also studied. Based on dictamnine, a natural alkaloid, two novel eligible derivatives are designed, synthesized and evaluated, which verifies our prediction. Multiple computational approaches and experimental combinations probably provide a train of thought from both static and dynamic views to modify or design appropriate inhibitors on the basis of specific binding and transportation features.

ALS-Linked A315T and A315E Mutations Enhance β-Barrel Formation of the TDP-43307-319 Hexamer: A REST2 Simulation Study.

Pathogenic mutations of transactivation response element DNA-binding protein 43 (TDP-43) are closely linked with amyotrophic lateral sclerosis (ALS). It was recently reported that two ALS-linked familial mutants A315T and A315E of TDP-43307-319 peptides can self-assemble into oligomers including tetramers, hexamers, and octamers, among which hexamers were suggested to form the β-barrel structure. However, due to the transient nature of oligomers, their conformational properties and the atomic mechanisms underlying the β-barrel formation remain largely elusive. Herein, we investigated the hexameric conformational distributions of the wild-type (WT) TDP-43307-319 fragment and its A315T and A315E mutants by performing all-atom explicit-solvent replica exchange with solute tempering 2 simulations. Our simulations reveal that each peptide can self-assemble into diverse conformations including ordered β-barrels, bilayer β-sheets and/or monolayer β-sheets, and disordered complexes. A315T and A315E mutants display higher propensity to form β-barrel structures than the WT, which provides atomic explanation for their enhanced neurotoxicity reported previously. Detailed interaction analysis shows that A315T and A315E mutations increase inter-molecular interactions. Also, the β-barrel structures formed by the three different peptides are stabilized by distinct inter-peptide side-chain hydrogen bonding, hydrophobic, and aromatic stacking interactions. This study demonstrates the enhanced β-barrel formation of the TDP-43307-319 hexamer by the pathogenic A315T and A315E mutations and reveals the underlying molecular determinants, which may be helpful for in-depth understanding of the ALS-mutation-induced neurotoxicity of TDP-43 protein.

Oxidation of thymol catalysed by a water-soluble Cu(II)-adipate-diphenylamine complex in a biphasic medium

A metal–organic framework involving a dicarboxylate (adipic acid) and dipyridylamine (dpya), [Cu2(dpya)(µ-adipate)].2ClO4·2H2O, has been synthesized by one-pot reaction and structurally characterized by X-ray diffraction. Pentacoordinated Cu(II) dimer complex links the adjacent Cu(dpya) units through chelating carboxylate oxygens of adipate dianion in a coordination pattern with the metal center. The centrosymmetric adipate-bridged dinuclear complex cations [Cu2(dpya)(µ-adipate)]2+ are assembled into pseudo-2D supramolecular networks through aromatic stacking interactions (4.108 Å) and also hydrogen bondings with counter ion with the coordinated water molecule. The catalytic performance of the compound was investigated for thymol (T) oxidation in organic solvents and water/hexane biphasic systems. Its selectivity was measured as 100 % for T to thymoquinone (TQ). A novel, simple, and efficient catalyst system (TOF = 400 h−1) was developed for the oxidation of T into a valuable derivate, TQ, using TBHP with subs./cat.(100) in a water/hexane biphasic system at 70 οC.

The first marine dual-drug cocrystal of cytarabine with 5-fluorouracil having synergistic antitumor effects shows superior biopharmaceutical peculiarities by oral administration

In order to highlight the advantages of cocrystallization technique in perfecting in vitro/vivo natures of marine drug cytarabine (ARC), and fill the gap of the research of marine pharmaceutical cocrystals with synergistic antitumor effects, the first dual-drug cocrystal simultaneously containing ARC and antitumor drug 5-fluorouracil (FU), viz. ARC-FU, is successfully designed and assembled. The accurate structure is perfectly resolved by single-crystal X-ray diffraction and other approaches. The analytical outcomes demonstrate that the codrug cocrystal consists of ARC and FU with a molar ratio of 1:1, in which FU molecule plays an important role by participating in the formation of both “pyrimidine-pyrimidine” and “pyrimidine-sugar” cyclic hydrogen-bonding systems with ARC molecules. In the cocrystal, there are twofold hydrogen-bonding helixes of ARC molecules and a whole three-dimensional hydrogen-bonding network which also contains the aromatic stacking interaction between pyrimidine rings of both components. Such structural feature and aggregation model have crucial influences on the improvements of in vitro/vivo properties, which is methodically verified by the combination of theoretical analyses and experimental measurements. The in vitro studies exhibit the suitably reduced solubility and obviously increased permeability for the cocrystal that is in accord with the theoretical prediction. Importantly, the ameliorated in vitro peculiarities realize in vivo pharmacokinetic optimization including the extended residence time and enhanced relative bioavailability. Of greater significance, ARC exerts synergistic antitumor effects in association with FU that brings about potentiation of cell growth inhibition with lower IC50. Thus, this research not only provides a novel crystalline form for ARC with forward-looking development value, but also breaks new ground for the development of synergistic antitumor pharmaceutical cocrystals with marine characteristics.

Structure-based rational design of a short-chain dehydrogenase/reductase for improving activity toward mycotoxin patulin

Patulin is a fatal mycotoxin that is widely detected in drinking water and fruit-derived products contaminated by diverse filamentous fungi. CgSDR from Candida guilliermondii represents the first NADPH-dependent short-chain dehydrogenase/reductase that catalyzes the reduction of patulin to the nontoxic E-ascladiol. To elucidate the catalytic mechanism of CgSDR, we solved its crystal structure in complex with cofactor and substrate. Structural analyses indicate that patulin is situated in a hydrophobic pocket adjacent to the cofactor, with the hemiacetal ring orienting toward the nicotinamide moiety of NADPH. In addition, we conducted structure-guided engineering to modify substrate-binding residue V187 and obtained variant V187F, V187K and V187W, whose catalytic activity was elevated by 3.9-, 2.2- and 1.7-fold, respectively. The crystal structures of CgSDR variants suggest that introducing additional aromatic stacking or hydrogen-bonding interactions to bind the lactone ring of patulin might account for the observed enhanced activity. These results illustrate the catalytic mechanism of SDR-mediated patulin detoxification for the first time and provide the upgraded variants that exhibit tremendous potentials in industrial applications.

Spontaneous Transfer of Indocyanine Green from Liposomes to Albumin Is Inhibited by the Antioxidant α-Tocopherol.

Indocyanine Green (ICG) is a clinically approved organic dye with near-infrared absorption and fluorescence. Over the years, many efforts to improve the photophysical and pharmacokinetic properties of ICG have investigated numerous nanoparticle formulations, especially liposomes with membrane-embedded ICG. A series of systematic absorption and fluorescence experiments, including FRET experiments using ICG as a fluorescence energy acceptor, found that ICG transfers spontaneously from liposomes to albumin protein residing in the external solution with a half-life of ∼10 min at 37 °C. Moreover, transfer of ICG from liposome membranes to external albumin reduces light-activated leakage from thermosensitive liposomes with membrane-embedded ICG. A survey of lipophilic liposome additives discovered that the presence of clinically approved antioxidant, α-tocopherol, greatly increases ICG retention in the liposomes (presumably by forming favorable aromatic stacking interactions), inhibits ICG photobleaching and prevents albumin-induced reduction of light-triggered liposome leakage. This new insight will help researchers with the specific task of optimizing ICG-containing liposomes for fluorescence imaging or phototherapeutics. More broadly, the results suggest a broader design concept concerning light triggered liposome leakage, that is, proximity of the light absorbing dye to the bilayer membrane is a critical design feature that impacts the extent of liposome leakage.

The Pink Box: Exclusive Homochiral Aromatic Stacking in a Bis-perylene Diimide Macrocycle.

This work showcases chiral complementarity in aromatic stacking interactions as an effective tool to optimize the chiroptical and electrochemical properties of perylene diimides (PDIs). PDIs are a notable class of robust dye molecules and their rich photo- and electrochemistry and potential chirality make them ideal organic building blocks for chiral optoelectronic materials. By exploiting the new bay connectivity of twisted PDIs, a dynamic bis-PDI macrocycle (the “Pink Box”) is realized in which homochiral PDI–PDI π–π stacking interactions are switched on exclusively. Using a range of experimental and computational techniques, we uncover three important implications of the macrocycle’s chiral complementarity for PDI optoelectronics. First, the homochiral intramolecular π–π interactions anchor the twisted PDI units, yielding enantiomers with half-lives extended over 400-fold, from minutes to days (in solution) or years (in the solid state). Second, homochiral H-type aggregation affords the macrocycle red-shifted circularly polarized luminescence and one of the highest dissymmetry factors of any small organic molecule in solution (glum = 10–2 at 675 nm). Finally, excellent through-space PDI–PDI π-orbital overlap stabilizes PDI reduced states, akin to covalent functionalization with electron-withdrawing groups.

Study on the self-assembly of aromatic antimicrobial peptides based on different PAF26 peptide sequences

Abstract Antimicrobial peptide (AMP) self-assembly is an effective way to synthesis antimicrobial biomaterials. In previous studies, we found PAF26 AMP (Ac-RKKWFW-NH2) and its derivative K2–F2 peptide (Ac-KKRKKWFWFF-NH2) could both self-assemble into hydrogels, but they had distinct microscopic structures. Therefore, in this work five PAF26 peptide derivatives with different numbers of aromatic amino acids are designed to better understand the self-assembly mechanism of aromatic AMP. The transmission electron microscopy, infrared spectroscopy, circular dichroism, and fluorescence spectroscopy characterizations are carried out to study the microscope structure, secondary conformation, and molecular interactions. It is found that the five peptide derivatives have different microscopic structures, and the number of aromatic amino acids will affect the peptide hydrogen bonding and aromatic stacking interactions, causing significant differences in the secondary conformation and microscopic structure. This work will enhance the comprehension of aromatic AMP self-assembly.

Quantitative Investigation of Halogen and Hydrogen Bonding in 2‐Chloro, 4‐X‐Benzoic Acids

AbstractThe crystal structure, Hirshfeldsurface analysis, topological analysis of the electron density and total interaction energies of four compounds, 2‐Chloro, 4‐X‐Benzoic Acids (where X=I, Br, Cl and F) have been analysed. The packing similarity was evaluated in all compounds using theXPacanalysis. The qualitative information about intermolecular interactions is derived from the crystal structure and Hirshfeld surface analyses whereas quantitative information are determined by the QTAIM analysis as well as total interaction energies fromCrystalExplorer. The topological properties are estimated for all compounds in both crystal geometry and gas phase usingTOPONDandAIMALL, respectively. The carboxylic acid O−H⋅⋅⋅O HB dimers, C−H⋅⋅⋅O HBs and Cπ⋅⋅⋅Cπaromatic stacking interactions are found to be common interactions in all compounds. The topological properties and bond paths demonstrate them as non‐covalent stabilizing interactions in the crystalline state. The hierarchy of interactions concerning their strength is observed in the following order such that O−H⋅⋅⋅O HB dimers>Cπ⋅⋅⋅Cπaromatic stacking interactions>C−H⋅⋅⋅O HBs>Type II X⋅⋅⋅Cl interactions and C−H⋅⋅⋅Cl HBs>Type I homo‐halogen X⋅⋅⋅X interactions in all compounds. Additionally, the strength of Type I homo‐halogen X⋅⋅⋅X interactions vary in the order: I⋅⋅⋅I>Br⋅⋅⋅Br>Cl⋅⋅⋅Cl>F⋅⋅⋅F. The hierarchy of interactions is further supported by molecular electrostatic potential surfaces associated with both positive and negative potential regions.

Elucidating the mechanism of nucleation inhibition of pathology crystallization of gout based on the evidence from amorphous form and in solution.

The first gout attack in a hyperuricaemic patient may be regarded as a nucleation event which is caused by monosodium urate monohydrate (MSUM) deposition in the synovial fluid. The effect of Tailor-Made Inhibition (TMI) may be effective as drugs for the prevention of aberrant nucleation and crystallization. Therefore, the understanding of the underlying mechanisms in inhibiting the MSUM nucleation by TMI has proven to be of great significance. Yet most of the published studies about nucleation inhibition have tended to focus on simpler molecular models with a hydrogen-bonded acceptor and donor, which may be not suitable for the uric acid molecule with multiple hydrogen-bonded acceptors and donors under physiological conditions. Herein, the mechanisms of nucleation inhibition of MSUM were explored in a simulated biological environment (0.15 M Na+ and pH 7.40) in the presence and absence of TMI. And the evidence of nucleation inhibition by TMI in solution and the amorphous form of MSUM was investigated by HNMR, IR, Raman, PXRD, Dynamic light scattering (DLS), induction time measurements, and density functional theory (DFT) calculations. Results showed that the inhibition comes from a combination of kinetic and thermodynamic effects, with an impact of kinetics as the TMI inhibition effects far exceeded what could be accounted for by changes in usual factors of classical nucleation theory. The data demonstrated that the complex between urate and TMI disturbed the formation of two-dimensional sheets of sodion and purine rings parallel to the (011) plane and further impeded the formation of a three-dimensional structure with aromatic stacking interactions in solution. To our knowledge, the nucleation inhibition of TMI is achieved by suppressing interplanar stacking, which is a mechanism proposed for the first time.

Aromatic interactions directing peptide nano-assembly.

Self-assembly is a process of spontaneous organization of molecules as a result of non-covalent interactions. Organized self-assembly at the nano level is emerging as a powerful tool in the bottom-up fabrication of functional nanostructures for targeted applications. Aromatic π-π stacking plays a significant role by facilitating the persistent supramolecular association of individual subunits to the self-assembled structures of high stability. Understanding, the supramolecular chemistry of the materials interacting through aromatic interactions, is of tremendous interest in not only constructing functional materials but also in revealing the mechanism of molecular assembly in living organisms. This chapter aims to focus on understanding the potential role of π-π interactions in directing and regulating the self-assembly of peptide nanostructures. The scope of the chapter starts with an outline of the history and mechanism of the aromatic π-π interactions. It progresses through the design strategy for the assembly of peptides containing aromatic rings, the conditions affecting the aromatic stacking interactions, their resulting nanoassemblies, properties, and applications. The properties and applications of the supramolecular materials formed through the aromatic stacking interactions are highlighted to provide an increased understanding of the role of weak interactions in the design and construction of novel functional materials.