Hydrogen-bonding Contacts Research Articles

Enhanced enzymatic activity and conformational stability of catalase in presence of tetrahedral DNA nanostructures: A biophysical and kinetic study

The emergence of DNA nanotechnology has shown enormous potential in a vast array of applications, particularly in the medicinal and theranostics fields. Nevertheless, the knowledge on the biocompatibility between DNA nanostructures and cellular proteins is largely unknown. Herein, we report the biophysical interaction between proteins (circulatory protein bovine serum albumin, BSA, and the cellular enzyme bovine liver catalase, BLC) and tetrahedral DNA (tDNA), which are well-known nanocarriers for therapeutics. Interestingly, the secondary conformation of BSA or BLC was unaltered in the presence of tDNAs which supports the biocompatible property of tDNA. In addition, thermodynamic studies showed that the binding of tDNAs with BLC has a stable non-covalent interaction via hydrogen bond and van der Waals contact, which is indicative of a spontaneous reaction. Furthermore, the catalytic activity of BLC was increased in the presence of tDNAs after 24 h of incubation. These findings indicate that the presence of tDNA nanostructures not only ensures a steady secondary conformation of proteins, but also stabilize the intracellular proteins like BLC. Surprisingly, our investigation discovered that tDNAs have no effect on albumin proteins, either by interfering or by adhering to the extracellular proteins. These findings will aid in the design of future DNA nanostructures for biomedical applications by increasing the knowledge on the biocompatible interaction of tDNAs with biomacromolecules.

Understanding the impact of halogen functional group (Br, Cl, F, OH) in amprenavir ligand of the HIV protease

We focused our attention towards the most dreadful disease that threatens the mankind of 20th century - Acquired immunodeficiency syndrome (AIDS), caused through the human immunodeficiency virus (HIV) and a sexually transmitted infection (STI). In this study, our foremost interest was to identify the potency and stability of HIV ligand- Amprenavir (APV) and its modelled functional group (Br, Cl, F, CF3, CH3, NH2) ligands through halogen and hydrogen bond contact, which will have a clear portrait on the structure activity of protein ligand interactions. This will assist chemist in synthesizing novel APV ligands, which are expected to inhibit the activity of HIV-1 protease enzyme. The binding strength of Amprenavir ligand with interacting hinge region amino acid side chains: Isoleucine (ILE 147, 150, 184), Valine (VAL 82), Alanine (ALA 28), Aspartic acid (25, 30, 125, 130) and Glycine (GLY 127, 149) were understood through interaction energy calculations at HF, B3LYP, M052X, MP2 level of theories for different basis set (6-311 G**, LANL2DZ). The present work will reveal an understandable picture about the halogen and hydrogen bond interaction that grip the contact of ligand and amino acids in the hinge region. Overall the Halogen atom (Br, Cl, F) functional groups improved the binding strength of APV in HIV protease; which provide a new novel path for the functional group preference on the ligand that enclose perfectly with the amino acid in the hinge region. Communicated by Ramaswamy H. Sarma

Hydrogen-bonding enables two-dimensional metal/semiconductor tunable contacts approaching the quantum limit and the modified Schottky-Mott limit simultaneously.

Achieving efficient electrical contacts in two-dimensional (2D) semiconductors is increasingly critical with the continuous scaling down of transistors. van der Waals (vdW) contacts with weak Fermi-level pinning are still hindered by the additional contact resistance due to weak interlayer coupling. Here, based on first-principles, we propose to exploit hydrogen-bonding interactions to intrinsically overcome the inherent vdW gap. Various metal/semiconductor heterojunctions with hydroxyl-terminated MXenes as the metal electrode demonstrate clean Ohmic contacts with ultralow contact resistance approaching the quantum limit via strong hydrogen-bonding of O-H⋯X (X = N, O, S, Se, etc.) at the interface. Hydrogen-bonding contacts are further shown to be an advantageous approach to achieve near-perfect N-type contacts for emerging 2D nitride, oxide, halide, and chalcogenide semiconductors that can simultaneously approach the modified Schottky-Mott limit. We finally discuss the general design concepts for hydrogen-bonding contacts, demonstrating their potential to go beyond vdW contacts in achieving ideal electrical contacts in 2D semiconductors.

Conformational Dynamics of mCherry Variants: A Link between Side-Chain Motions and Fluorescence Brightness.

The 3-fold higher brightness of the recently developed mCherry-XL red fluorescent protein (FP) compared to its progenitor, mCherry, is due to a significant decrease in the nonradiative decay rate underlying its increased fluorescence quantum yield. To examine the structural and dynamic role of the four mutations that distinguish the two FPs and closely related variants, we employed microsecond time scale, all-atom molecular dynamics simulations. The simulations revealed that the I197R mutation leads to the formation of multiple hydrogen-bonded contacts and increased rigidity of the β-barrel. In particular, mCherryXL showed reduced nanosecond time scale breathing of the gap between the β7 and β10-strands, which was previously shown to be the most flexible region of mCherry. Together with experimental results, the simulations also reveal steric interactions of residue 161 and a network of hydrogen-bonding interactions of the chromophore with residues at positions 59, 143, and 163 that are critical in perturbing the chromophore electronic structure. Finally, we shed light on the conformational dynamics of the conserved residues R95 and S146, which are hydrogen-bonded to the chromophore, and provide physical insights into the observed photophysics. To the best of our knowledge, this is the first study that evaluates the conformational space for a set of closely related FPs generated by directed evolution.

From PEF to PBF: What difference does the longer alkyl chain make a computational spectroscopy study of poly(butylene 2,5-furandicarboxylate).

This work explores the conformational preferences and the structure-property correlations of poly(butylene 2,5-furandicarboxylate) (PBF), a longer chain analogue of the most well-known biobased polyester from the furan family, poly(ethylene 2,5-furandicarboxylate) (PEF). A thorough computational spectroscopic study-including infrared, Raman and inelastic neutron scattering spectroscopy, combined with discrete and periodic density functional theory calculations-allowed the identification of dominant structural motifs in the amorphous and crystalline regions. Discrete calculations and vibrational spectroscopy of semi-crystalline and amorphous samples strongly support the predominance of gauche, trans, gauche conformations of the butylene glycol fragment in both the crystalline and amorphous domains. In what concerns the furandicarboxylate fragment, amorphous domains are dominated by syn,syn conformations, while in the crystalline domains the anti,anti forms prevail. A possible crystalline structure-built from these conformational preferences and including a network of C-H···O hydrogen bond contacts-was optimized using periodic density functional theory. This proposed crystal structure avoids the unrealistic structural features of the previously proposed X-ray structure, provides an excellent description of the inelastic neutron scattering spectrum of the semi-crystalline form, and allows the correlation between microscopic structure and macroscopic properties of the polymer.

Inhibition and Mechanism of Plasmodium falciparum Hypoxanthine-Guanine-Xanthine Phosphoribosyltransferase.

Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase (PfHGXPRT) is essential for purine salvage of hypoxanthine into parasite purine nucleotides. Transition state analogue inhibitors of PfHGXPRT are characterized by kinetic analysis, thermodynamic parameters, and X-ray crystal structures. Compound 1, 9-deazaguanine linked to an acyclic ribocation phosphonate mimic, shows a kinetic Ki of 0.5 nM. Isothermal titration calorimetry (ITC) experiments of 1 binding to PfHGXPRT reveal enthalpically driven binding with negative cooperativity for the binding of two inhibitor molecules in the tetrameric enzyme. Crystal structures of 1 bound to PfHGXPRT define the hydrogen bond and ionic contacts to complement binding thermodynamics. Dynamics of ribosyl transfer from 5-phospho-α-d-ribosyl 1-pyrophosphate (PRPP) to hypoxanthine were examined by 18O isotope exchange at the bridging phosphoryl oxygen of PRPP pyrophosphate. Rotational constraints or short transition state lifetimes prevent torsional rotation and positional isotope exchange of bridging to nonbridging oxygen in the α-pyrophosphoryl group. Thermodynamic analysis of the transition state analogue and magnesium pyrophosphate binding reveal random and cooperative binding to PfHGXPRT, unlike the obligatory ordered reaction kinetics reported earlier for substrate kinetics.

Comparison on inhibitory effect and mechanism of inhibitors on sPPO and mPPO purified from ‘Lijiang snow’ peach by combining multispectroscopic analysis, molecular docking and molecular dynamics simulation

The inhibition mechanisms of soluble PPO (sPPO) by l-cysteine, reduced glutathione and thiourea, and membrane-bound (mPPO) by l-cysteine, reduced glutathione, thiourea, anisaldehyde and cinnamaldehyde were investigated by combining multispectroscopic analysis and computational simulations. Reduced glutathione showed the strongest inhibitory effect, with IC50 of 0.46 and 0.94 mM, respectively. The multispectral results showed that all inhibitors inhibited activity by destroying the secondary and tertiary structure, and the structure of sPPO were more easily affected. Docking showed that hydrogen bond and metal contact were the main driving force for inhibitors binding to sPPO and mPPO, respectively. Simulation showed that sPPO-inhibitor system had more fluctuation than mPPO-inhibitor system, indicating easier inhibition of sPPO activity. This work revealed that the structural differences between sPPO and mPPO led to different inhibition mechanisms of PPOs by inhibitors at the molecular level, which could provide the guidance for the selection of inhibitors in fruit and vegetable processing.

The first crystal structure of a xylobiose-bound xylobiohydrolase with high functional specificity from the bacterial glycoside hydrolase family 30, subfamily 10.

Xylobiose is a prebiotic sugar that has applications in functional foods. This report describes the first X-ray crystallographic structure models of apo and xylobiose-bound forms of a xylobiohydrolase (XBH) from Acetivibrio clariflavus. This xylan-active enzyme, a member of the recently described glycoside hydrolase family 30 (GH30), subfamily 10, phylogenetic clade has been shown to strictly release xylobiose as its primary hydrolysis product. Inspection of the apo structure reveals a glycone region X2 -binding slot. When X2 binds, the non-reducing xylose in the -2 subsite is highly coordinated with numerous hydrogen bond contacts while contacts in the -1 subsite mostly reflect interactions typical for GH30 and enzymes in clan A of the carbohydrate-active enzymes database (CAZy). This structure provides an explanation for the high functional specificity of this new bacterial GH30 XBH subfamily.

Characterization in Inhibitory Effectiveness of Carbamazepine in Voltage-Gated Na+ and Erg-Mediated K+ Currents in a Mouse Neural Crest-Derived (Neuro-2a) Cell Line.

Carbamazepine (CBZ, Tegretol®) is an anticonvulsant used in the treatment of epilepsy and neuropathic pain; however, several unwanted effects of this drug have been noticed. Therefore, the regulatory actions of CBZ on ionic currents in electrically excitable cells need to be reappraised, although its efficacy in suppressing voltage-gated Na+ current (INa) has been disclosed. This study was undertaken to explore the modifications produced by CBZ on ionic currents (e.g., INa and erg-mediated K+ current [IK(erg)]) measured from Neuro-2a (N2a) cells. In these cells, we found that this drug differentially suppressed the peak (transient, INa(T)) and sustained (late, INa(L)) components of INa in a concentration-dependent manner with effective IC50 of 56 and 18 μM, respectively. The overall current–voltage relationship of INa(T) with or without the addition of CBZ remained unchanged; however, the strength (i.e., ∆area) in the window component of INa (INa(W)) evoked by the short ascending ramp pulse (Vramp) was overly lessened in the CBZ presence. Tefluthrin (Tef), a synthetic pyrethroid, known to stimulate INa, augmented the strength of the voltage-dependent hysteresis (Hys(V)) of persistent INa (INa(P)) in response to the isosceles-triangular Vramp; moreover, further application of CBZ attenuated Tef-mediated accentuation of INa(P)’s Hys(V). With a two-step voltage protocol, the recovery of INa(T) inactivation seen in Neuro-2a cells became progressively slowed by adding CBZ; however, the cumulative inhibition of INa(T) evoked by pulse train stimulation was enhanced during exposure to this drug. Neuro-2a-cell exposure to CBZ (100 μM), the magnitude of erg-mediated K+ current measured throughout the entire voltage-clamp steps applied was mildly inhibited. The docking results regarding the interaction of CBZ and voltage-gate Na+ (NaV) channel predicted the ability of CBZ to bind to some amino-acid residues in NaV due to the existence of a hydrogen bond or hydrophobic contact. It is conceivable from the current investigations that the INa (INa(T), INa(L), INa(W), and INa(P)) residing in Neuro-2a cells are susceptible to being suppressed by CBZ, and that its block on INa(L) is larger than that on INa(T). Collectively, the magnitude and gating of NaV channels produced by the CBZ presence might have an impact on its anticonvulsant and analgesic effects occurring in vivo.

Proximicin A-C as prospective HER2-positive and negative breast cancer drugs: Molecular docking and in silico ADME modeling

Breast cancer is the second leading cause of cancer-related death among women worldwide. Proximicin A-C are bioactive chemicals produced by the marine Verrucosispora strain, which have been shown to have potent cytostatic effect against human breast cancer [MCF 7]. HER2 (Human epidermal growth factor receptor 2) is a gene that has been linked to breast cancer development. The study’s goals are to (1) forecast the intensity of binding affinity and interactions between HER2 and proximicin A-C, and (2) analyze ADME characteristics of proximicin A-C (Absorption, Distribution, Metabolism, and Excretion). The CB-Dock web service was used to dock proximicin A-C and commonly used breast cancer medicines Neratinib (Nerlynx) and Talazoparib against HER2, and protein-ligand interaction findings were collected via the protein-ligand interaction profiler (PLP) web server. The SwissADME web server was used to investigate ADME properties of the substances. In terms of docking, proximicin A has a vina score of -8.6, proximicin B and C has a score of -10, Talazoparib has a vina score of -8.5, and Neratinib (Nerlynx) has a vina score of -10.2 on CB-Dock. This means that proximicin B and C bind to HER2 more strongly than proximicin A and Talazoparib. Furthermore, their high binding affinity is nearly equivalent to Neratinibs (Nerlynx). Talazoparib has a lower binding affinity for HER2 than proximicin A. With HER2, all three chemicals have a strong hydrogen bond and hydrophobic contact. SwissADME estimated that all three substances follow the Lipinski rule (RO5) and have a bioavailability score of 0.55. They don’t have any structural issue in medicinal chemistry (no alerts in PAINS and Brenk forecasts), and their synthetic accessibility scales range from 3 to 3.5. Only proximicin A, on the other hand, has the leadlikeness feature. All three drugs failed to cross the blood-brain barrier (BBB) in terms of pharmacokinetics. Proximicin A has a high absorption rate in the GI tract, whereas proximicin B-C has a low absorption rate in the GI tract (GI). Similarly, proximicin A is neither a P-gp substrate nor a CYP1A2, CYP2C19, CYP2C9, CYP2D6, or CYP3A4 inhibitor. Proximicin B-C, on the other hand, are P-gp substrates, and proximicin C is an inhibitor of all provided CYP enzymes, whilst proximicin B inhibits only three. Overall, proximicin A-C could be used as a possible breast cancer therapeutic candidate. Proximicin B-C will outperform proximicin A in terms of therapeutic efficacy. Proximicin A, on the other hand, will have better ADME qualities than Proximicin B-C. This study will provide the lead information for developing a new breast cancer medication with a good pharmacological profile.

Structural Enzymology of the Cysteine Tryptophylquinone (CTQ) Enzyme GoxA

GoxA from Pseudoalteromonas luteoviolaceae belongs to a recently identified family of enzymes (the LodA‐like proteins) that utilize a post‐translationally derived cysteine tryptophylquinone (CTQ) cofactor for catalysis. In contrast to other tryptophylquinone enzymes, GoxA acts as an oxidase rather than a dehydrogenase, using molecular oxygen to catalyze the oxidative deamination of glycine to produce ammonia, glyoxylate and hydrogen peroxide. The crystal structure of this enzyme revealed a homotetramer with a novel alpha helical domain and extensive inter‐subunit interactions, which account for the positive cooperativity observed toward its substrate by steady‐state kinetics. Soaking GoxA crystals in glycine results in a dramatic color change from yellow to blue, indicating the formation of an unusual intermediate at the CTQ site that was also detected in solution. The structure of this intermediate reveals a Schiff‐base formed between the substrate and CTQ that is stabilized by numerous hydrogen bond contacts with residues both in the active site and from a neighboring protomer. The kinetics and structures of active site mutants reveal the roles of specific residues in substrate binding, cooperativity, and catalysis, and allowed for the detection of another intermediate in the GoxA reaction pathway. This combination of kinetics, spectroscopy and X‐ray crystallography has allowed for the construction of a detailed reaction mechanism for this unusual enzyme with high‐resolution structures now available for key intermediates.

A kind of HIV-1 protease inhibitors containing phenols with antiviral activity against DRV-resistant variants

Based upon the preliminary design of enhancing genetic barrier to drug-resistant viral mutants by maximizing hydrogen-bonding or other van der Waals contacts, we have designed, synthesized and biologically evaluated a new class of HIV-1 protease inhibitors with phenol derived P2 ligands and nitro or halogens in P2′ ligands. Results indicate that a majority of inhibitors exhibit robust enzyme inhibitory with IC50 values in picomolar or single digit nanomolar ranges. Among which, compound 17d displays potency with IC50 value of 21 pM and high protease selectivity. Of note, 17d exhibits greater antiviral activity against the DRV-resistant variant than the efficacy against the wild type virus. Furthermore, the molecular modeling studies demonstrate important interactions between 17d and the active sites of both the wild-type and DRV-resistant HIV-1 protease, as well as furnish insights for further optimization of new inhibitors.

Supramolecule self-assembly approach to direct Z-scheme TiO2/g-C3N4 heterojunctions for efficient photocatalytic degradation of emerging phenolic pollutants

To improve the visible-light photocatalytic oxidation activity of anatase TiO2 or graphitic carbon nitride (g-C3N4) towards organic pollutants, the present work develops a supramolecule self-assembly approach combined with thermal polycondensation to construct direct Z-scheme-dictated TiO2/g-C3N4 heterojunctions. This in-situ route not only leads to the TiO2/g-C3N4 with porous sheet-like nanostructures but also establishes hydrogen-bonded intimate interfacial contact between TiO2 and g-C3N4. The TiO2/g-C3N4 heterojunctions demonstrate significantly enhanced visible-light photocatalytic activity in the degradation of emerging phenolic pollutants, acetaminophen and methylparaben, as compared with TiO2, P25 TiO2 and g-C3N4; additionally, TiO2-to-g-C3N4 molar ratio in the heterojunctions influences the activity remarkably. This enhanced photocatalytic oxidation performance is mainly ascribed to the direct Z-scheme-dictated charge carrier transfer mechanism, driven by well-matched energy band structures of TiO2 and g-C3N4 as well as the intimate interfacial contact between TiO2 and g-C3N4. Accordingly, the spatial separation of the photogenerated charge carriers is boosted; simultaneously, strong redox ability of electrons on conduction band of g-C3N4 and holes on valence band of TiO2 is retained. Therefore, abundant reactive oxygen species like •O2− anion radicals and •OH radicals are generated. These reactive oxygen species together with holes are responsible for the elevated photocatalytic oxidation performance of TiO2/g-C3N4 heterojunctions.

Early aggregation mechanism of Aβ16−22 revealed by Markov state models

Aβ16–22 is believed to have critical role in early aggregation of full length amyloids that are associated with the Alzheimer's disease and can aggregate to form amyloid fibrils. However, the early aggregation mechanism is still unsolved. Here, multiple long-term molecular dynamics simulations combining with Markov state model were used to probe the early oligomerization mechanism of Aβ16−22 peptides. The identified dimeric form adopted either globular random-coil or extended β-strand like conformations. The observed dimers of these variants shared many overall conformational characteristics but differed in several aspects at detailed level. In all cases, the most common type of secondary structure was intermolecular antiparallel β-sheets. The inter-state transitions were very frequent ranges from few to hundred nanoseconds. More strikingly, those states which contain fraction of β secondary structure and significant amount of extended coiled structures, therefore exposed to the solvent, were majorly participated in aggregation. The assembly of low-energy dimers, in which the peptides form antiparallel β sheets, occurred by multiple pathways with the formation of an obligatory intermediates. We proposed that these states might facilitate the Aβ16−22 aggregation through a significant component of the conformational selection mechanism, because they might increase the aggregates population by promoting the inter-chain hydrophobic and the hydrogen bond contacts. The formation of early stage antiparallel β sheet structures is critical for oligomerization, and at the same time provided a flat geometry to seed the ordered β-strand packing of the fibrils. Our findings hint at reorganization of this part of the molecule as a potentially critical step in Aβ aggregation and will insight into early oligomerization for large β amyloids.

Crystal structure and Hirshfeld surface analysis of 5-acetyl-3-amino-6-methyl-N-phenyl-4-[(E)-2-phenyl-ethen-yl]thieno[2,3-b]pyridine-2-carbox-amide.

The asymmetric unit of the title compound, C25H21N3O2S, comprises four mol-ecules. Their conformations differ primarily in the orientations of the styryl and the N-phenyl-carboxamido groups. In the crystal, inter-molecular N-H⋯N, C-H⋯O and C-H⋯S hydrogen-bonding contacts as well a C-H⋯π(ring) inter-actions lead to the formation of a layer structure parallel to (010). Hirshfeld surface analysis revealed that H⋯H inter-actions represent the main contributions to the crystal packing.

Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids.

The role of G-quadruplexes in human cancers is increasingly well-defined. Accordingly, G-quadruplexes can be suitable drug targets and many small molecules have been identified to date as G-quadruplex binders, some using computer-based design methods and co-crystal structures. The role of bound water molecules in the crystal structures of G-quadruplex-small molecule complexes has been analyzed in this study, focusing on the water arrangements in several G-quadruplex ligand complexes. One is the complex between the tetrasubstituted naphthalene diimide compound MM41 and a human intramolecular telomeric DNA G-quadruplex, and the others are in substituted acridine bimolecular G-quadruplex complexes. Bridging water molecules form most of the hydrogen-bond contacts between ligands and DNA in the parallel G-quadruplex structures examined here. Clusters of structured water molecules play essential roles in mediating between ligand side chain groups/chromophore core and G-quadruplex. These clusters tend to be conserved between complex and native G-quadruplex structures, suggesting that they more generally serve as platforms for ligand binding, and should be taken into account in docking and in silico studies.

Synthesis, crystal structure and phase transition in a perovskite type (CH3NH3)2M(X)2(Y)2(M=Sn; X=SCN; Y=Cl)

The exploration of ferroelectric hybrid materials is highly appealing due to their great technological significance. In line with this, we herein report the development of a new ferroelectric relaxor: (CH3NH3)2Sn(SCN)2Cl2 was synthesized and studied by single-crystal X-ray diffraction, powder XRD, Differential scanning calorimetry (DSC), IR spectroscopy and dielectric measurements. The phase purity was confirmed by Rietveld refinement of the X-ray powder diffraction pattern. It crystallizes, at room temperature, in the orthorhombic system with the Pnm21 space group. The crystal structure is formed of discrete ionic entities (CH3NH3)+ and (Sn(SCN)2Cl2)2-. The methylammonium cations are bonded to these chains by hydrogen-bonding contacts. DSC measurement shows that this compound exhibits a diffuse ferro–paraelectric phase transition around 355 K. Dielectric study exhibits a relaxor behavior characterized by the transition temperature shifts toward higher temperature with the rise of frequency. This behavior was validated by the modified Curie–Weiss law. The diffuseness parameter was the γ is approach to 1.96 at 2000 KHz.

Ring Size as an Independent Variable in Cyclooligomeric Depsipeptide Antiarrhythmic Activity.

Hit-to-lead studies employ a variety of strategies to optimize binding to a target of interest. When a structure for the target is available, hypothesis-driven structure-activity relationships (SAR) are a powerful strategy for refining the pharmacophore to achieve robust binding and selectivity characteristics necessary to identify a lead compound. Recrafting the three-dimensional space occupied by a small molecule, optimization of hydrogen bond contacts, and enhancing local attractive interactions are traditional approaches in medicinal chemistry. Ring size, however, is rarely able to be leveraged as an independent variable because most hits lack the symmetry required for such a study. Our discovery that the cyclic oligomeric depsipeptide ent-verticilide inhibits mammalian cardiac ryanodine receptor calcium release channels with submicromolar potency provided an opportunity to explore ring size as a variable, independent of other structural or functional group changes. We report here that ring size can be a critical independent variable, suggesting that modest conformational changes alone can dramatically affect potency.

Ab initio study of nuclear quantum effects on sub- and supercritical water.

The structures of water in the ambient, subcritical, and supercritical conditions at various densities were studied systematically by ab initio path integral molecular dynamics simulations. It was found that the nuclear quantum effects (NQEs) have a significant impact on the structure of hydrogen bonds in close contact, not only in the ambient condition but also in the sub- and supercritical conditions. The NQEs on the structure beyond the hydrogen bond contact are important in ambient water, but not much for water in the sub- and supercritical conditions. The NQEs are furthermore important for determining the number of hydrogen bonds in the ambient conditions, and this role is, however, diminished in the sub- and supercritical conditions. The NQEs do, nevertheless, show their importance in determining the intramolecular structure of water and the close contact structures of the hydrogen bonds, even at sub- and supercritical conditions. Using the RPBE-D3 functional, the computed radial distribution functions for ambient water are in excellent agreement with experimental data, upgrading our previous results using the BLYP-D2 functional [Machida et al., J. Chem. Phys. 148, 102324 (2018)]. The computed radial distribution functions for water in the sub- and supercritical conditions were carefully compared with experiment. In particular, we found that the first peak in hydrogen pair distribution functions matches only when the NQEs are taken into account.

DFT-Based Stereochemical Rationales for the Bifunctional Brønsted Acid/Base-Catalyzed Diastereodivergent and Enantioselective aza-Henry Reactions of α-Nitro Esters.

A pair of chiral bis(amidine) [BAM] proton complexes provide reagent (catalyst)-controlled, highly diastereo- and enantioselective direct aza-Henry reactions leading to α-alkyl-substituted α,β-diamino esters. A C2-symmetric ligand provides high anti-selectivity, while a nonsymmetric congener exhibits syn-selectivity in this example of diastereodivergent, enantioselective catalysis. A detailed computational analysis is reported for the first time, one that supports distinct models for selectivity resulting from the more hindered binding cavity of the C1-symmetric ligand. Binding in this congested pocket accommodates four hydrogen bond contacts among ligands and substrates, ultimately favoring a pre-syn arrangement highlighted by pyridinium-azomethine activation and quinolinium-nitronate activation. The complementary transition states reveal a wide range of alternatives. Comparing the C1- and C2-symmetric catalysts highlights distinct electrophile binding orientations despite their common hydrogen bond donor-acceptor features. Among the factors driving unusual high syn-diastereoselection are favorable dispersion forces that leverage the anthracenyl substituent of the C1-symmetric ligand.