Intramolecular Hydrogen-bonding Network Research Articles

Enhancement of metal‐binding affinity for Cu+/Cu2+ complexes by hydrogen bond network

AbstractUsing density functional theory, polyols were used as model ligands for Cu+/Cu2+ complexes to study the role of the hydrogen bond network on the metal binding affinity. In addition to the gas phase studies, the calculations were performed in 1‐decanol and DMSO solvents. The Cu2+ complexes were the most stable complexes with the highest bond dissociation energies (BDE). The presence of three H‐bonds in the first shell increased BDE values up to 17.99 and 57.07 kcal/mol for Cu+ and Cu2+ complexes in the gas phase, respectively, whereas the presence of another three H‐bonds in the second shell increased BDE values up to 7.27 and 24.35 kcal/mol for Cu+ and Cu2+ complexes in the gas phase, respectively. Therefore, this H‐bond network caused, for example, a more stable Cu+ complex with a formation constant of 1.4 × 1017 times. The natural bond orbital (NBO), atoms in molecules (AIM), and reduced density gradient (RDG) analyses showed that the intramolecular hydrogen bond network led to the enhancement of metal‐binding affinity.

Molecular mechanism underlying the increased risk of colorectal cancer metastasis caused by single nucleotide polymorphisms in LI-cadherin gene

LI-cadherin is a member of the cadherin superfamily. LI-cadherin mediates Ca2+-dependent cell–cell adhesion through homodimerization. A previous study reported two single nucleotide polymorphisms (SNPs) in the LI-cadherin-coding gene (CDH17). These SNPs correspond to the amino acid changes of Lys115 to Glu and Glu739 to Ala. Patients with colorectal cancer carrying these SNPs are reported to have a higher risk of lymph node metastasis than patients without the SNPs. Although proteins associated with metastasis have been identified, the molecular mechanisms underlying the functions of these proteins remain unclear, making it difficult to develop effective strategies to prevent metastasis. In this study, we employed biochemical assays and molecular dynamics (MD) simulations to elucidate the molecular mechanisms by which the amino acid changes caused by the SNPs in the LI-cadherin-coding gene increase the risk of metastasis. Cell aggregation assays showed that the amino acid changes weakened the LI-cadherin-dependent cell–cell adhesion. In vitro assays demonstrated a decrease in homodimerization tendency and MD simulations suggested an alteration in the intramolecular hydrogen bond network by the mutation of Lys115. Taken together, our results indicate that the increased risk of lymph node metastasis is due to weakened cell–cell adhesion caused by the decrease in homodimerization tendency.

Azo group-enabled metal- and oxidant-free alkenyl C–H thiolation: Access to stereodefined tetrasubstituted acyclic olefins

Metal- and oxidant-free alkenyl C–H thiolation enabled by the azo group had been established for the modular synthesis of tetrasubstituted acyclic olefins. The reaction was performed under mild reaction conditions with a broad substrate scope. The intramolecular 6-membered hydrogen-bonding network accounts for the observed excellent stereo-control.

Unveiling the Shape of N-Acetylgalactosamine: A Cancer-Associated Sugar Derivative.

In the present work, we report the first rotational study of N-acetylgalactosamine, a cancer-associated sugar derivative, by means of high-resolution rotational spectroscopy. Two different conformers have been conclusively characterized using broadband Fourier transform microwave spectroscopy coupled with a laser ablation vaporization system. Additionally, we performed a comprehensive analysis of the intramolecular interactions that govern these structures, which allowed us to both characterize the existence of intramolecular hydrogen bond networks that drive the intrinsic conformation panorama of N-acetylgalactosamine and further rationalize the biological role of this aminosugar derivative as part of the Tn antigen.

Universal multifunctional hydrogen bond network construction strategy for enhanced aqueous Zn2+/proton hybrid batteries

Aqueous rechargeable zinc-ion batteries (AZIBs) are in a period of vigorous development due to their unparalleled advantages, including low cost, high safety and environmentally friendly etc. However, the structural damage, dissolution, low conductivity of electrode materials and slow diffusion kinetics of Zn2+ ions carriers significantly limit the development of AZIBs. Herein, for the first time, we propose a general strategy for constructing multifunctional intramolecular hydrogen bond network through N-H∙∙∙O (NH4+) and O-H∙∙∙O (H2O) bonds while suppressing material dissolution (V, Mn species), enhancing the stability of layered structures, and accelerating the rapid diffusion of protons. To better reveal the hydrogen bond and enhanced proton transport, a range of in/ex-situ characterization techniques in conjunction with DFT calculations have been implemented. As a proof of concept, this strategy has proven to be universally applicable, with both vanadium oxide (400.6 Wh kg−1/6489.3 W kg−1, 85% over 4000 cycles) and manganese oxide (433.6 Wh kg−1/2972.8 W kg−1, 100% after 500 cycles) achieving significant electrochemical performance improvements, particularly in terms of rate performance and cycle performance, which are better than most comparable materials. The insights obtained in this study have deepened the understanding based on the hydrogen bond in AZIBs and also brought new opportunities for improving the energy density of other types of aqueous batteries in the future.

Catalytic Conversion of Sugar-Derived Polyhydroxy Acid to Trimellitate

Biomass resources, especially carbohydrates derived from cellulose and hemicellulose, could be utilized as an alternative feedstock for the production of fuel and bulk chemicals. Here, we present a sustainable route for the synthesis of trimethyl trimellitate from 1,6-dimethyl galactarate, the diester of sugar-derived polyhydroxy galactaric acid. The process starts with the deoxydehydration reaction of 1,6-dimethyl galactarate to form dimethyl muconate with an 84% yield. Nuclear magnetic resonance (NMR) and density functional theory results show that the molecular structure of 1,6-dimethyl galactarate possesses strong intramolecular hydrogen bond networks and is endowed with chemical recalcitrance. ¹H NMR tests of variable catalyst concentrations reveal that the introduction of ammonium perrhenate could weaken the intramolecular hydrogen bond effect and activate the chemically inert molecules. The Diels–Alder reaction of muconate and acrylate is conducted efficiently to produce a substituted cyclohexene intermediate without any catalyst used, and a 72% yield of the target product, trimethyl trimellitate, is obtained via the dehydro-aromatization reaction of the cycloadduct. This new approach provides a template path for the synthesis of aromatic oxygenated compounds and would promote the development of green polymer materials.

N-Alkylated Aromatic Poly- and Oligoamides.

N-alkylated aromatic poly- and oligoamides are a particular class of abiotic foldamers that is deprived of the capability of forming intramolecular hydrogen-bonding networks to stabilize their tri-dimensional structure. The alkylation of the backbone amide nitrogen atoms greatly increases the chemical diversity accessible for aromatic poly- and oligoamides. However, the nature and the conformational preferences of the N,N-disubstituted amides profoundly modify the folding properties of these aromatic poly- and oligoamides. In this Review, representative members of this class of aromatic poly- and oligoamides will be highlighted, among them N-alkylated phenylene terephthalamides, benzanilides, pyridylamides, and aminomethyl benzamide oligomers. The principal synthetic pathways to the main classes of N-alkylated aromatic polyamides with narrow to broad molecular-weight distribution, or oligoamides with specific sequences, will be detailed and their foldameric properties will be discussed. The Review will end by describing the few applications reported to date and future prospects for the field.

Strong Reduction of the Chain Rigidity of Hyaluronan by Selective Binding of Ca2+ Ions.

The biological functions of natural polyelectrolytes are strongly influenced by the presence of ions, which bind to the polymer chains and thereby modify their properties. Although the biological impact of such modifications is well recognized, a detailed molecular picture of the binding process and of the mechanisms that drive the subsequent structural changes in the polymer is lacking. Here, we study the molecular mechanism of the condensation of calcium, a divalent cation, on hyaluronan, a ubiquitous polymer in human tissues. By combining two-dimensional infrared spectroscopy experiments with molecular dynamics simulations, we find that calcium specifically binds to hyaluronan at millimolar concentrations. Because of its large size and charge, the calcium cation can bind simultaneously to the negatively charged carboxylate group and the amide group of adjacent saccharide units. Molecular dynamics simulations and single-chain force spectroscopy measurements provide evidence that the binding of the calcium ions weakens the intramolecular hydrogen-bond network of hyaluronan, increasing the flexibility of the polymer chain. We also observe that the binding of calcium to hyaluronan saturates at a maximum binding fraction of ∼10–15 mol %. This saturation indicates that the binding of Ca2+ strongly reduces the probability of subsequent binding of Ca2+ at neighboring binding sites, possibly as a result of enhanced conformational fluctuations and/or electrostatic repulsion effects. Our findings provide a detailed molecular picture of ion condensation and reveal the severe effect of a few, selective and localized electrostatic interactions on the rigidity of a polyelectrolyte chain.

Multi PCET in symmetrically substituted benzimidazoles.

Proton-coupled electron transfer (PCET) reactions depend on the hydrogen-bond connectivity between sites of proton donors and acceptors. The 2-(2′-hydroxyphenyl) benzimidazole (BIP) based systems, which mimic the natural TyrZ-His190 pair of Photosystem II, have been useful for understanding the associated PCET process triggered by one-electron oxidation of the phenol. Substitution of the benzimidazole by an appropriate terminal proton acceptor (TPA) group allows for two-proton translocations. However, the prototropic properties of substituted benzimidazole rings and rotation around the bond linking the phenol and the benzimidazole can lead to isomers that interrupt the intramolecular hydrogen-bonded network and thereby prevent a second proton translocation. Herein, a strategic symmetrization of a benzimidazole based system with two identical TPAs yields an uninterrupted network of intramolecular hydrogen bonds regardless of the isomeric form. NMR data confirms the presence of a single isomeric form in the disubstituted system but not in the monosubstituted system in certain solvents. Infrared spectroelectrochemistry demonstrates a two-proton transfer process associated with the oxidation of the phenol occurring at a lower redox potential in the disubstituted system relative to its monosubstituted analogue. Computational studies support these findings and show that the disubstituted system stabilizes the oxidized two-proton transfer product through the formation of a bifurcated hydrogen bond. Considering the prototropic properties of the benzimidazole heterocycle in the context of multiple PCET will improve the next generation of novel, bioinspired constructs built by concatenated units of benzimidazoles, thus allowing proton translocations at nanoscale length.

Rotational spectrum and intramolecular hydrogen bonding in 1,2-butanedithiol

The jet-cooled rotational spectrum of 1,2-butanedithiol was observed in the frequency region 2–8 GHz. Two conformers were detected for the molecule, corresponding to anti- and gauche-carbon molecular skeletons, both featuring a gauche arrangement of the two thiol groups. All 13C and 34S monosubstituted isotopologues were additionally assigned in natural abundance for the most stable anti isomer, while only the two 34S species were detected for the weaker gauche conformation. The structural analysis included ground-state effective structures, isotopic substitution coordinates, B3LYP-D3(BJ) density functional molecular orbital calculations and non-covalent interactions mapping with NCIPlot. The structural data confirm that the two thiol groups synchronize their orientation either parallel or antiparallel to support intramolecular S–H⋯S weak hydrogen bonding, reminiscent of the intramolecular hydrogen bond networks observed in adjacent alcohol groups. DFT calculations on 1,2-butanediol and 1,2-ethanedithiol offered structural comparisons with the title compound.

Polyketides and a Dihydroquinolone Alkaloid from a Marine-Derived Strain of the Fungus Metarhizium marquandii.

Three new natural products (1-3), including two butenolide derivatives (1 and 2) and one dihydroquinolone derivative (3), together with nine known natural products were isolated from a marine-derived strain of the fungus Metarhizium marquandii. The structures of the new compounds were unambiguously deduced by spectroscopic means including HRESIMS and 1D/2D NMR spectroscopy, ECD, VCD, OR measurements, and calculations. The absolute configuration of marqualide (1) was determined by a combination of modified Mosher's method with TDDFT-ECD calculations at different levels, which revealed the importance of intramolecular hydrogen bonding in determining the ECD features. The (3R,4R) absolute configuration of aflaquinolone I (3), determined by OR, ECD, and VCD calculations, was found to be opposite of the (3S,4S) absolute configuration of the related aflaquinolones A-G, suggesting that the fungus M. marquandii produces aflaquinolone I with a different configuration (chiral switching). The absolute configuration of the known natural product terrestric acid hydrate (4) was likewise determined for the first time in this study. TDDFT-ECD calculations allowed determination of the absolute configuration of its chirality center remote from the stereogenic unsaturated γ-lactone chromophore. ECD calculations aided by solvent models revealed the importance of intramolecular hydrogen bond networks in stabilizing conformers and determining relationships between ECD transitions and absolute configurations.

Crystal Structure and Strong Piezoelectricity of New Amino Acid Based Hybrid Crystals: [H-β-(3-Pyridyl)-Ala-OH][ClO4] and [H-β-(4-Pyridyl)-Ala-OH][ClO4

The new amino acid based [H-β-(3-pyridyl)-Ala-OH][ClO4] and [H-β-(4-pyridyl)-Ala-OH][ClO4] crystals were synthesized, and their structure and functional piezoelectric properties were investigated in detail. Both analogs crystallize in the polar, piezoelectric P21 space group. Piezoresponse force microscopy (PFM) measurements revealed that shear piezoelectric coefficient of [H-β-(3-Pyridyl)-Ala-OH][ClO4] crystal is more than twice that in the widely used transducer material lithium niobate, LiNbO3. The crystal structures of both perchlorate derivatives were determined, and the influence of the inter- and intramolecular hydrogen bond network on piezoelectricity of crystals were discussed. The existence of the intramolecular hydrogen bonding was confirmed by means of IR spectroscopy measurements. Thermogravimetric (TGA) technique was applied to study the thermal behavior of title crystals.

The p12 subunit of human polymerase δ uses an atypical PIP box for molecular recognition of proliferating cell nuclear antigen (PCNA)

Human DNA polymerase δ is essential for DNA replication and acts in conjunction with the processivity factor proliferating cell nuclear antigen (PCNA). In addition to its catalytic subunit (p125), pol δ comprises three regulatory subunits (p50, p68, and p12). PCNA interacts with all of these subunits, but only the interaction with p68 has been structurally characterized. Here, we report solution NMR-, isothermal calorimetry-, and X-ray crystallography-based analyses of the p12-PCNA interaction, which takes part in the modulation of the rate and fidelity of DNA synthesis by pol δ. We show that p12 binds with micromolar affinity to the classical PIP-binding pocket of PCNA via a highly atypical PIP box located at the p12 N terminus. Unlike the canonical PIP box of p68, the PIP box of p12 lacks the conserved glutamine; binds through a 2-fork plug made of an isoleucine and a tyrosine residue at +3 and +8 positions, respectively; and is stabilized by an aspartate at +6 position, which creates a network of intramolecular hydrogen bonds. These findings add to growing evidence that PCNA can bind a diverse range of protein sequences that may be broadly grouped as PIP-like motifs as has been previously suggested.

Macromolecular Crowding Tunes Protein Stability by Manipulating Solvent Accessibility.

In all intracellular processes, protein structure and dynamics are subject to the influence of macromolecular crowding (MC). Here, the impact of MC agents of different types and sizes on the model protein Bacillus subtilis Cold shock protein B (BsCspB) during both thermal and chemical denaturation have been comprehensively investigated. We consistently reveal a distinct stabilization of BsCspB in a manner dependent on the MC concentration but not on viscosity, polarity, or size of the MC agent used. This general stabilization has been decoded by use of NMR spectroscopy, through monitoring of chemical shift (CS) perturbations and the intramolecular hydrogen‐bonding networks, as well as local protection of amide protons against exchange with solvent protons. Whereas CSs and hydrogen‐bonding networks are not systematically affected in the presence of MC, we detected a pronounced reduction in exchange in loop regions of BsCspB. We conclude that this reduced accessibility of solvent protons is a key parameter for the increases in protein stability seen under MC.

Potent, multi-target serine protease inhibition achieved by a simplified β-sheet motif.

Engagement of an extended β-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like β-sheet to enzyme inhibition. Here we report the crystal structure of an simplified β-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by β–sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.

Pressure- and Temperature-Dependent Structural Stability of LLM-105 Crystal

The new energetic material 2,6-diamino-3,5-dinitropyrazine-1-oxide (C4H4N6O5, LLM-105) maintains its structural stability under high pressure below 30 GPa at room temperature or in the temperature range from 513 to 5 K with ambient pressure based on the high pressure or the cryogenic X-ray diffraction patterns. One structural phase transition occurs at about 30 GPa and is confirmed by the pressure-dependent Raman and infrared spectra. The structure of the LLM-105 crystal shows anisotropic compressibility under pressure in the order βb > βa > βc and anisotropic thermal expansion in the order αb > αc ≈ αa. A Debye temperature of 1225 K is obtained for this crystal based on the lattice parameters at different pressures or temperatures. The experimental data reveal that compression is a better method to reduce the volume of the LLM-105 crystal compared with cooling. Raman and infrared spectra at extreme conditions suggest that the structural stability is contributed to the stronger inter- and intramolecular hydrogen-bonding networks within the LLM-105 crystal. The symmetric and asymmetric stretching modes of amino groups are coupled and it can improve the understanding of pressure evolution of the LLM-105 crystal. The bond constants of amino groups with different pressures and temperatures are also obtained.

Revisiting the Case of an Intramolecular Hydrogen Bond Network Forming Four- and Five-Membered Rings in d-Glucose.

The conformational behavior of cyclic monosaccharides has been widely studied over the past years, but there is no general agreement about which effects are in fact responsible for the observed conformational preferences. A recent microwave spectroscopy study determined the conformational equilibrium of d-glucose in the gas phase with a preference for a counterclockwise arrangement of the hydroxyl groups. Nevertheless, the effects that control this orientation are still uncertain because the role of intramolecular hydrogen bonds (IHBs), electrostatic and steric repulsions is not clear. This work reports a density functional theory approach based on the conformational energies of d-glucose and of some derivatives in which the anomeric hydroxyl is replaced with hydrogen (H, small and not prone to participate in proton transfer), fluorine (F, small, electronegative, and as capable as OH of forming hydrogen bonds as a proton acceptor), and chlorine (Cl, big and not anticipated to be involved in effective hydrogen bond formation) to obtain insights into the effects of the substituent at the anomeric carbon on the arrangement of the hydroxyl groups in d-glucose. The nature of the substituents at this position is crucial to determine the orientation of the remaining hydroxyl groups. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses, in addition to NMR chemical shift calculations, have been provided to support the conformational energy outcomes. Overall, the results agree with the lack of IHBs forming four- and five-membered rings in d-glucose and emphasize that steric and electrostatic repulsions involving the hydroxyl groups in the clockwise orientation are driving forces of the conformational behavior.

Contribution of an unusual CDR2 element of a single domain antibody in ricin toxin binding affinity and neutralizing activity.

Ricin toxin's enzymatic subunit (RTA) has been subjected to intensive B cell epitope mapping studies using a combination of competition ELISAs, hydrogen exchange-mass spectrometry and X-ray crystallography. Those studies identified four spatially distinct clusters (I-IV) of toxin-neutralizing epitopes on the surface of RTA. Here we describe A9, a new single domain camelid antibody (VHH) that was proposed to recognize a novel epitope on RTA that straddles clusters I and III. The X-ray crystal structure of A9 bound to RTA (2.6 Å resolution) revealed extensive antibody contact with RTA's β-strand h (732 Å2 buried surface area; BSA), along with limited engagement with α-helix D (90 Å2) and α-helix C (138 Å2). Collectively, these contacts explain the overlap between epitope clusters I and III, as identified by competition ELISA. However, considerable binding affinity, and, consequently, toxin-neutralizing activity of A9 is mediated by an unusual CDR2 containing five consecutive Gly residues that interact with α-helix B (82 Å2), a known neutralizing hotspot on RTA. Removal of a single Gly residue from the penta-glycine stretch in CDR2 reduced A9's binding affinity by 10-fold and eliminated toxin-neutralizing activity. Computational modeling indicates that removal of a Gly from CDR2 does not perturb contact with RTA per se, but results in the loss of an intramolecular hydrogen bond network involved in stabilizing CDR2 in the unbound state. These results reveal a novel configuration of a CDR2 element involved in neutralizing ricin toxin.

Direct conversion of cellulose to sorbitol via an enhanced pretreatment with ionic liquids

ABSTRACTBACKGROUNDDirect conversion of cellulose into platform chemicals, is regarded as one of the most promising aspects of biomass resource utilization. However, the development of direct conversion of cellulose to high value‐added chemicals such as sorbitol still remains a tremendous problem owing to the robust structure of cellulose to resist degradation.RESULTSIn this study, ball‐milled microcrystalline cellulose was dissolved in ionic liquids, and finally converted to sorbitol smoothly through hydrolytic hydrogenation processes. Both ball‐milling and ionic liquids dissolution can effectively destroy the strong inter‐ and intramolecular hydrogen bond network formed between hydroxyl groups within cellulose. Furthermore, water‐soluble ionic cellulose came into being due to the dissolution of cellulose in ionic liquids, which increased the contact of cellulose to catalyst remarkably. The crystalline index of cellulose can be reduced from 79.9% to 3.2% under an optimum ball‐milling time of 4 h, and the preferred cellulose dissolution solvent was selected to be [Amim]Cl. Finally, the final product, sorbitol was successfully synthesized over the catalysis of Nafion NR50 and Ru/AC (active carbon) with the sorbitol yield to be 34.3% at 150 °C for 1 h.CONCLUSIONThis study proposed a novel approach about direct conversion of cellulose to sorbitol with ionic liquids as well as extended the application of ionic liquids in the field of conversion of renewable biomass to platform chemicals. © 2018 Society of Chemical Industry

Disease-Causing Mutations in the G Protein Gαs Subvert the Roles of GDP and GTP

The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Gαs. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Gαs through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Gαs that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase-activating activity of Gαs bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Gαs can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins.