Direct Hydrogen Bonds Research Articles

Quest for Zeolite-like Supramolecular Assemblies: Self-Assembly of Metal-Organic Squares via Directed Hydrogen Bonding.

Our conceived approach based on the directed assembly of functional metal-organic squares (MOSs), 4-membered ring (4MR) building units, permitted the construction of two novel zeolite-like supramolecular assemblies (ZSAs), namely [Co4 (ImDC)4 (En)4 ]⋅9 H2 O⋅1.5 DMF (ZSA-10) and [Co4 (ImDC)4 (En)4 ]⋅7 H2 O (ZSA-11) (H3 ImDC=4,5-imidazoledicarboxylic acid, En=ethylenediamine, DMF=N,N-dimethylformamide). The elected MOSs encompass both trans- and cis-coordinated nodes, offering complementary peripheral functional groups for their directed assembly into zeolite-like topologies via supramolecular hydrogen bonding interactions. Distinctly, ZSA-10 possesses the underling MER zeolite topology and is the only pure MER framework material (without any supporting templates) exhibiting permanent porosity up to now. ZSA-11 has the underlying ABW topology together with one type of narrow channel.

Quest for Zeolite‐like Supramolecular Assemblies: Self‐Assembly of Metal–Organic Squares via Directed Hydrogen Bonding

AbstractOur conceived approach based on the directed assembly of functional metal–organic squares (MOSs), 4‐membered ring (4MR) building units, permitted the construction of two novel zeolite‐like supramolecular assemblies (ZSAs), namely [Co4(ImDC)4(En)4]⋅9 H2O⋅1.5 DMF (ZSA‐10) and [Co4(ImDC)4(En)4]⋅7 H2O (ZSA‐11) (H3ImDC=4,5‐imidazoledicarboxylic acid, En=ethylenediamine, DMF=N,N‐dimethylformamide). The elected MOSs encompass both trans‐ and cis‐coordinated nodes, offering complementary peripheral functional groups for their directed assembly into zeolite‐like topologies via supramolecular hydrogen bonding interactions. Distinctly, ZSA‐10 possesses the underling MER zeolite topology and is the only pure MER framework material (without any supporting templates) exhibiting permanent porosity up to now. ZSA‐11 has the underlying ABW topology together with one type of narrow channel.

Dynamics of Ionic Interactions at Protein-Nucleic Acid Interfaces.

ConspectusMolecular association of proteins with nucleic acids is required for many biological processes essential to life. Electrostatic interactions via ion pairs (salt bridges) of nucleic acid phosphates and protein side chains are crucial for proteins to bind to DNA or RNA. Counterions around the macromolecules are also key constituents for the thermodynamics of protein–nucleic acid association. Until recently, there had been only a limited amount of experiment-based information about how ions and ionic moieties behave in biological macromolecular processes. In the past decade, there has been significant progress in quantitative experimental research on ionic interactions with nucleic acids and their complexes with proteins. The highly negatively charged surfaces of DNA and RNA electrostatically attract and condense cations, creating a zone called the ion atmosphere. Recent experimental studies were able to examine and validate theoretical models on ions and their mobility and interactions with macromolecules. The ionic interactions are highly dynamic. The counterions rapidly diffuse within the ion atmosphere. Some of the ions are released from the ion atmosphere when proteins bind to nucleic acids, balancing the charge via intermolecular ion pairs of positively charged side chains and negatively charged backbone phosphates. Previously, the release of counterions had been implicated indirectly by the salt-concentration dependence of the association constant.Recently, direct detection of counterion release by NMR spectroscopy has become possible and enabled more accurate and quantitative analysis of the counterion release and its entropic impact on the thermodynamics of protein–nucleic acid association. Recent studies also revealed the dynamic nature of ion pairs of protein side chains and nucleic acid phosphates. These ion pairs undergo transitions between two major states. In one of the major states, the cation and the anion are in direct contact and form hydrogen bonds. In the other major state, the cation and the anion are separated by water. Transitions between these states rapidly occur on a picosecond to nanosecond time scale. When proteins interact with nucleic acids, interfacial arginine (Arg) and lysine (Lys) side chains exhibit considerably different behaviors. Arg side chains show a higher propensity to form rigid contacts with nucleotide bases, whereas Lys side chains tend to be more mobile at the molecular interfaces. The dynamic ionic interactions may facilitate adaptive molecular recognition and play both thermodynamic and kinetic roles in protein–nucleic acid interactions.

Unraveling Decisive Structural Parameters for the Self-Assembly of Supramolecular Polymer Bottlebrushes Based on Benzene Trisureas

By introducing strong directed hydrogen bonds to an amphiphilic polymer, we demonstrate that phase transitions from spherical to cylindrical morphologies in aqueous solutions can significantly be shifted to favor the assembly of supramolecular polymer bottlebrushes. In water, a forced self-assembly of polymers into cylindrical structures remains a challenge as the often required hydrophobic shielding induces forces, which tend to minimize the surface area. The herein presented novel benzene trisureas can overcome these limitations due to strong hydrogen bonds and alter the morphology to cylinders despite an unfavorable packing parameter, which dominated the previously reported trisamide analogues. The systematic variation of composition and architecture revealed that a transition to spherical morphologies still occurs, but the phase-transition boundaries appear to be shifted to tolerate larger hydrophilic polymer chains. The strength of the directing interactions appears to be decisive for the shift, though we additionally observed that any restrictions of lateral aggregation can diminish the effect of the directing hydrogen bonds. Overall, the straightforward synthesis and versatile design render the presented systems an interesting blueprint for the development of more advanced supramolecular polymer bottlebrushes and multifunctional nanostructures.

Preparation of solution-grown lozenge-shaped poly(p-phenylene terephthalamide) single crystals and their structural stabilization by heat treatment

In this study, the preparation of poly (p-phenylene terephthalamide) (PPTA) single crystals was examined using crystallization from dilute solutions in concentrated sulfuric acid. Lozenge-shaped PPTA single crystals were successfully prepared using a self-seeding method with a low degree of supercooling, and they consisted of modification I crystals. The a-axis direction of the crystal corresponded to the long diagonal direction of the rhombus, the b-axis direction with the short diagonal direction, and the PPTA molecular chain direction (the c-axis direction) with the crystal's thickness direction. In addition, the PPTA single crystals had a (110) growth plane, where the thickness of each single crystal was approximately equal to the molecular chain length of the PPTA. Upon heat treatment of the PPTA single crystals, the symmetry changed from P1a1 to the more stable P11n. In addition, the heat treatment caused a difference in the density of each symmetric crystal, resulting in crack formation along the b-axis direction, which is the hydrogen-bonding direction. However, the heat treatment did not change the thickness of the PPTA single crystals. Conversely, the isothermal crystallization of the PPTA caused progression in the crystallization only under a high degree of supercooling, thus yielding plate-like PPTA crystals that consisted of modification II crystals. In these plate-like PPTA crystals, the length corresponded to the crystal a-axis direction, and the electron diffraction pattern was broad. Furthermore, the equilibrium dissolution temperature of the PPTA single crystals was discussed.

Electrochemically Controlled Polymerization through the Use of Redox-Responsive Ureidopyrimidinones for Supramolecular Polymers.

Supramolecular polymers are constructed along weaker, non-covalent interactions such as hydrogen-bonding. Compared to conventional polymers where monomer units react to form covalent bonds, non-covalent interactions of monomer units grant these supramolecular polymers dynamic behavior. One example of these systems that utilizes non-covalent interactions to construct supramolecular polymers are the well-investigated ureidopyrimidinones, UPy. UPy’s dimerize along their 4 strong directional hydrogen bonds in non-polar organic solvents. UPy’s have been covalently linked at the ends of smaller monomer chains so as to function as chain-linkers in the construction of larger polymer structures under favorable dimerization conditions. One interest in the use of these systems in supramolecular applications is their inherent ability of self-healing. Applying heat or mechanical stress to these systems will prevent polymerization at the H-bonds. However, upon relief of these external stimuli, H-bonding resumes. In this study, the use of electron transfer as an external stimulus to perturb dimerization and affect UPy chain polymerization will be explored. In order to exemplify the aims of this study, previously studied electroactive UPy’s will be investigated as redox-responsive chain terminators with regards to linear polymer chains that are functionalized with UPy units at their terminal ends, allowing for long-chain polymerization indicated by an increase in solution viscosity. In this study, a decrease in solution viscosity should be observed once these long chain bi-functionalized UPy polymers are in the presence of redox-responsive mono-functional UPy. Upon electrochemical oxidation / reduction of the mono-functional electroactive UPy units, an increase in viscosity is expected. The weakened H-bonding of the mono-functional UPy units will prevent chain termination and long-chain polymerization between bi-functional long chain UPy’s is expected to resume.

Solvation at metal/water interfaces: An ab initio molecular dynamics benchmark of common computational approaches.

Determining the influence of the solvent on electrochemical reaction energetics is a central challenge in our understanding of electrochemical interfaces. To date, it is unclear how well existing methods predict solvation energies at solid/liquid interfaces, since they cannot be assessed experimentally. Ab initio molecular dynamics (AIMD) simulations present a physically highly accurate, but also a very costly approach. In this work, we employ extensive AIMD simulations to benchmark solvation at charge-neutral metal/water interfaces against commonly applied continuum solvent models. We consider a variety of adsorbates including *CO, *CHO, *COH, *OCCHO, *OH, and *OOH on Cu, Au, and Pt facets solvated by water. The surfaces and adsorbates considered are relevant, among other reactions, to electrochemical CO2 reduction and the oxygen redox reactions. We determine directional hydrogen bonds and steric water competition to be critical for a correct description of solvation at the metal/water interfaces. As a consequence, we find that the most frequently applied continuum solvation methods, which do not yet capture these properties, do not presently provide more accurate energetics over simulations in vacuum. We find most of the computed benchmark solvation energies to linearly scale with hydrogen bonding or competitive water adsorption, which strongly differ across surfaces. Thus, we determine solvation energies of adsorbates to be non-transferable between metal surfaces, in contrast to standard practice.

The Structurally Unusual Retaining β‐Kdo Glycosyltransferase WbbB Uses a Double‐Displacement Mechanism with an Intermediate Adduct Rearrangement Step

WbbB is a modular, trifunctional glycosyltransferase (GT) which synthesizes lipopolysaccharide O‐antigen in Raoultella terrigena. The two C‐terminal WbbB GT domains build the polysaccharide repeat, while the N‐terminal GT domain acts as a terminator, adding a β‐Kdo (3‐deoxy‐d‐manno‐oct‐2‐ulosonic acid) residue to O3 to rhamnose as required for O‐antigen export. This N‐terminal GT domain is highly unusual in sequence and was not recognized as a GT by bioinformatics tools. The structure shows the dual Rossmann‐fold motifs characteristic of GT‐Bs, but with extensive deletions, insertions and rearrangements result in a unique architecture. The CMP‐binding site, however, retains motifs homologous to GT‐B sialyltransferases. WbbB is a retaining GT, transferring Kdo from the CMP‐®‐Kdo donor with net retention of anomeric configuration. All well‐characterized retaining GTs seem to employ a front‐side SNi substitution mechanism. This is somewhat surprising, as analogous retaining glycosyl hydrolases use a double‐displacement mechanism; here an essential catalytic acid residue attacks the donor saccharide to form a covalently bonded intermediate, with a second acidic residue acting as a general base to hydrolyse this adduct. We show, using mass spectrometry, that WbbB forms a Kdo adduct with Asp232 and its variants (D232N or D232C), while a D232A variant is both wholly inactive and forms no adduct. The x‐ray structure of D232N CMP‐®‐Kdo donor complex shows that the anomeric carbon of the donor is inaccessible to any potential acceptor but is instead positioned immediately in contact with, and in line with, the carboxylate of Asp232. Structures of D232N‐ and D232C‐Kdo adducts show that the Kdo adduct is rearranged into a second half‐site, interacting with a distinct set of catalytic residues. A ternary complex of D232C‐Kdo plus a synthetic acceptor shows that Glu158 forms direct hydrogen bonds with O3 of rhamnose, positioned adjacent to and in‐line with the anomeric carbon of Kdo, activating it for attack. Glu158 is also essential, with variants being wholly inactive. Together, this shows that WbbB uses a glycosyl hydrolase‐like double‐displacement mechanism. We propose that crowding around the anomeric carbon by the carboxylate group likely precludes retaining ulosonic acid transferases using the more straightforward SNi mechanism, while adduct rearrangement avoids having the acceptor compete with the leaving nucleotide for access to the anomeric carbon of the donor.Support or Funding InformationThis work was funded by an NSERC Discovery grant (04045‐2015) to MSK and support from the Canadian Glycomics Network (SD‐1) to TLL; TJBF is the recipient of a University of Guelph Graduate Excellence Entrance Scholarship and an Ontario Graduate Scholarship.

Charting Hydrogen Bond Anisotropy.

A hydrogen bond (HB) is an essential interaction in countless phenomena, regulating the chemistry of life. HBs are characterized by two features, strength and directionality, with a high degree of heterogeneity across different chemical groups. These characteristics are dependent on the electronic configuration of the atoms involved in the interaction, which, in turn, is influenced strongly by the local molecular environment. Studies based on the analysis of HB in the solid phase, such as X-ray crystallography, suffer from significant biases due to packing forces. These will tend to better describe strong HBs at the expenses of weak ones, which will be either distorted or under-represented. Using quantum mechanics (QM), we calculated interaction energies for about a hundred acceptors and donors in a rigorously defined set of geometries. We performed 180,000 independent QM calculations, covering all relevant angular components, mapping strength and directionality in a context free from external biases, with both single-site and cooperative HBs. By quantifying directionality, we show that there is no correlation with strength; therefore, these two components need to be addressed separately. Results demonstrate that there are very strong HB acceptors (e.g., dimethyl sulfoxide) with nearly isotropic interactions and weak ones (e.g., thioacetone) with a sharp directional profile. Similarly, groups can have comparable directional propensity but be very distant in the strength spectrum (e.g., thioacetone and pyridine). Results provide a new perspective on the way HB directionality is described, with implications for biophysics and molecular recognition that ultimately can influence chemical biology, protein engineering, and drug design.

Critical comparison of R[sbnd]X⋯Y and R[sbnd]H⋯Y directionality in halogen and hydrogen bonds using modern computational chemistry methods

Symmetry adapted perturbation theory anlysis and intermolecular overlap volume calculations are used to investigate the origins of halogen- and hydrogen bond directionality. The central finding is that exchange-repulsion is primarily responsible for destabilizing both types of interaction as the R-x⋯Y (x = H, Cl, Br) angle deviates from linearity. The particular shape of the electron density envelope on the halogen/hydrogen bond donor plays a large role in dictating the degree to which a complex is destabilized upon R-x⋯Y rotation, with halogen bonds exhibiting a roughly linear destabilization and hydrogen bonds exhibiting destabilization that is approximately quadratic.

Solvent influence on the crystal packing of 6-aminothiocytosine.

The crystal structures of 6-aminothiocytosine (systematic name: 4,6-diamino-1,2-dihydropyrimidine-2-thione, DAPMT, C4H6N4S), its hemihydrate (0.5H2O) and its dimethylformamide (DMF, C3H7NO) monosolvate were compared, and the influence of the type of solvent on the supramolecular motifs was analysed. In all three crystal structures, there are two symmetry-independent molecules (A and B), and these molecules are connected by three relatively short and directional hydrogen bonds to form chains of alternating A and B molecules. A further organization of these chains is dependent on the nature of the solvent molecule. In the unsolvated form, two orientations of the neighbouring chains are observed, and similar motifs - but only one per structure - can be observed in the solvated structures. These two different motifs can be connected by two different kinds of contacts, i.e. either π-π (hemihydrate) or staple-supported S...S (DMF). In the crystal structures, the O atoms of the solvent molecules are double acceptors of the same type of hydrogen bonds and bind the chains of DAPMT molecules into different motifs (dimeric or infinite chains). A Hirshfeld fingerprint analysis was used for visualization and additional interpretation of these results.

Excited state proton transfer processes of pyranine studied by femtosecond stimulated Raman spectroscopy

As one of the most fundamental processes, proton transfer reaction plays an important role in chemical and biological process, and to reveal the choreography of the proton motion intra- and intermolecularly, a spectroscopic technique capable of capturing molecular structural dynamics of excited-state proton transfer motions on an intrinsic time scale is needed. In this study, We utilize wavelength-tunable femtosecond stimulated Raman spectroscopy with a time resolution of ~100 fs, spectral resolution of 15 cm<sup>–1</sup> and spectral range of 400 cm<sup>–1</sup>—1800 cm<sup>–1</sup>, combined with traditional transient absorption spectroscopywith a time window between 0 and 600 ps to simultaneously achieve reaction dynamics for transient reactant and product of the photoacid pyranine (8-hydroxypyrene1, 3, 6-trisulfonic acid, HPTS) molecules undergoing excited-state proton transfer reaction in complex with water and acetate molecules. Marker bands attributed to the deprotonated form of HPTS in a frequency range from 400 cm<sup>–1</sup> to 1700 cm<sup>–1</sup> are obtained under the excitation of 400 nm laser pulses. The marker band at 1516 cm<sup>–1</sup>, which is assigned to phenolic ring carbon carbon double band stretching accompanied with carbon hydrogen in-plane rocking motions, exhibits complex rise and decay dynamics. The simultaneously observed excited-state Raman mode at 920 cm<sup>–1</sup> which is assigned to the excited carbon-carbon single bond stretch mode in the protonated acetic acid root molecule, helps us to clearly resolve the reaction rates of excited-state proton transfer. Based on the multi-exponential fitting results, the dynamics of excited-state Raman mode at 920 cm<sup>–1</sup> exhibits bi-exponential processes with time constants of ~470 fs and ~3 ps. The ultrafast time component indicates that the excited-state proton transfer originates from an HPTS-acetate complex, indicating that part of the ground-state HPTS molecules are in the “tight” hydrogen bonding configuration that can quickly shift the excited-state proton charge toward the acetate acceptor molecule through a direct hydrogen bond. The second slower time component implies a significant subpopulation of HPTS in the ground state, i.e. hydrogen bonds to an acetate ion via an intervening water molecule, and upon photo excitation, the proton transfers to the water solvent before proton is picked up by the acetate ion.

Closest-Packing Water Monolayer Stably Intercalated in Phyllosilicate Minerals under High Pressure.

The directional hydrogen-bond (HB) network and nondirectional van der Waals (vdW) interactions make up the specificity of water. Directional HBs could construct an ice-like monolayer in hydrophobic confinement even in the ambient regime. Here, we report a water monolayer dominated by vdW interactions confined in a phyllosilicate interlayer under high pressure. Surprisingly, it was in a thermodynamically stable state coupled with bulk water at the same pressure (P) and temperature (T), as revealed by the thermodynamic integration approach on the basis of molecular dynamics (MD) simulations. Both classical and ab initio MD simulations showed water O atoms were stably trapped and exhibited an ordered hexagonal closest-packing arrangement, but OH bonds of water reoriented frequently and exhibited a specific two-stage reorientation relaxation. Strikingly, hydration in the interlayer under high pressure had no relevance with surface hydrophilicity rationalized by the HB forming ability, which, however, determines wetting in the ambient regime. Intercalated water molecules were trapped by vdW interactions, which shaped the closest-packing arrangement and made hydration energetically available. The high pressure-volume term largely drives hydration, as it compensates the entropy penalty which is restricted by a relatively lower temperature. This vdW water monolayer should be ubiquitous in the high pressure but low-temperature regime.

Alteration of the groove width of DNA induced by the multimodal hydrogen bonding of denaturants with DNA bases in its grooves affects their stability

BackgroundDenaturants, namely, urea and guanidinium chloride (GdmCl) affect the stability as well as structure of DNA. Critical assessment of the role of hydrogen bonding of these denaturants with the different regions of DNA is essential in terms of its stability and structural aspect. However, the understanding of the mechanistic aspects of structural change of DNA induced by the denaturants is not yet well understood. MethodsIn this study, various spectroscopic along with molecular dynamics (MD) simulation techniques were employed to understand the role of hydrogen bonding of these denaturants with DNA bases in their stability and structural change. Results and conclusionIt has been found that both, GdmCl and urea intrude into groove region of DNA by striping surrounding water. The hydrogen bonding pattern of Gdm+ and urea with DNA bases in its groove region is multimodal and distinctly different from each other. The interaction of GdmCl with DNA is stabilized by electrostatic interaction whereas electrostatic and Lennard-Jones interactions both contribute for urea. Gdm+ forms direct hydrogen bond with the bases in the minor groove of DNA whereas direct and water assisted hydrogen bond takes place with urea. The hydrogen bond formed between Gdm+ with bases in the groove region of DNA is stronger than urea due to strong electrostatic interaction along with less self-aggregation of Gdm+ than urea. The distinct hydrogen bonding capability of Gdm+ and urea with DNA bases in its groove region affects its width differently. The interaction of Gdm+ decreases the width of the minor and major groove which probably increases the strength of hydrogen bond between the Watson-Crick base pairs of DNA leading to its stability. In contrast, the interaction of urea does not affect much to the width of the grooves except the marginal increase in the minor groove width which probably decreases the strength of hydrogen bond between Watson Crick base pairs leading to the destabilization of DNA. General significanceOur study clearly depicts the role of hydrogen bonding between DNA bases and denaturants in their stability and structural change which can be used further for designing of the guanidinium based drug molecules.

Molecular insight into a new low-affinity xylan binding module from the xylanolytic gut symbiont Roseburiaintestinalis.

Efficient capture of glycans, the prime metabolic resources in the human gut, confers a key competitive advantage for gut microbiota members equipped with extracellular glycoside hydrolases (GHs) to target these substrates. The association of glycans to the bacterial cell surface is typically mediated by carbohydrate binding modules (CBMs). Here, we report the structure of RiCBM86 appended to a GH family 10 xylanase from Roseburiaintestinalis. This CBM represents a new family of xylan binding CBMs present in xylanases from abundant and prevalent healthy human gut Clostridiales. RiCBM86 adopts a canonical β-sandwich fold, but shows structural divergence from known CBMs. The structure of RiCBM86 has been determined with a bound xylohexaose, which revealed an open and shallow binding site. RiCBM86 recognizes only a single xylosyl ring with direct hydrogen bonds. This mode of recognition is unprecedented amongst previously reported xylan binding type-B CBMs that display more extensive hydrogen-bonding patterns to their ligands or employ Ca2+ to mediate ligand-binding. The architecture of RiCBM86 is consistent with an atypically low binding affinity (KD about0.5mm for xylohexaose) compared to most xylan binding CBMs. Analyses using NMR spectroscopy corroborated the observations from the complex structure and the preference of RiCBM86 to arabinoxylan over glucuronoxylan, consistent with the largely negatively charged surface flanking the binding site. Mutational analysis and affinity electrophoresis established the importance of key binding residues, which are conserved in the family. This study provides novel insight into the structural features that shape low-affinity CBMs that mediate extended bacterial glycan capture in the human gut niche. DATABASES: Structural data are available in the protein data bank database under the accession number 6SGF. Sequence data are available in the GenBank database under the accession number EEV01588.1. The assignment of the Roseburiaintestinalis xylan binding module into the CBM86 new family is available in the CAZy database (http://www.cazy.org/CBM86.html).

A Porous and Solution-Processable Molecular Crystal Stable at 200 °C: The Surprising Donor–Acceptor Impact

We report a curious porous molecular crystal that is devoid of the common traits of related systems. Namely, the molecule does not rely on directional hydrogen bonds to enforce open packing, and it...

Neutron Compton Scattering: from proton momentum distribution to muonium hyperfine coupling constant in the isopropyl radical

We establish a fast and reliable benchmarking protocol for predictions of Muon Spin Resonance observables. To this end, we apply neutron Compton scattering (NCS) to study the nuclear momentum distributions of the proton and deuteron in the condensed phase of the isopropyl and d-isopropyl alcohols. By subtracting the time-of-flight NCS spectra of both compounds we demonstrate that the proton momentum distribution in the OH group of isopropanol and the deuteron momentum distribution in the OD group in d-isopropyl can be studied selectively. The site-selective application of the NCS method enables the calculation of the magnitude of the frequency isotope effect for the proton in OH along the hydrogen bond direction. By comparing the magnitude of the frequency isotope effect with values predicted for simple model potentials we are able to perform the appraisal of the degree of anharmonicity of the OH proton environment. Assuming that the effective potential felt by the OH proton along the hydrogen-bond direction can be satisfactorily described by the Morse potential, we are able to calculate its dissociation constant D and decay constant a. Finally, assuming that the same Morse potential describes the local binding of Muonium in the mioniated isopropyl radical, we are able to predict its width of momentum and position distributions and the kinetic and zero-point energy. Based on these results, we are able to provide a conservative bound for the magnitude of the isotope effect on the muonium hyperfine interaction without resorting to a complicated and computationally expensive methodology based on the application of path integrals.

Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI

Factor XI (FXI), the zymogen of activated FXI (FXIa), is an attractive target for novel anticoagulants because FXI inhibition offers the potential to reduce thrombosis risk while minimizing the risk of bleeding. BAY 1213790, a novel anti-FXIa antibody, was generated using phage display technology. Crystal structure analysis of the FXIa–BAY 1213790 complex demonstrated that the tyrosine-rich complementarity-determining region 3 loop of the heavy chain of BAY 1213790 penetrated deepest into the FXIa binding epitope, forming a network of favorable interactions including a direct hydrogen bond from Tyr102 to the Gln451 sidechain (2.9 Å). The newly discovered binding epitope caused a structural rearrangement of the FXIa active site, revealing a novel allosteric mechanism of FXIa inhibition by BAY 1213790. BAY 1213790 specifically inhibited FXIa with a binding affinity of 2.4 nM, and in human plasma, prolonged activated partial thromboplastin time and inhibited thrombin generation in a concentration-dependent manner.

Probing Molecular Nanostructures of Aromatic Terephthalic Acids Triggered by Intermolecular Hydrogen Bonds and Electrochemical Potential.

Self-assembly provides unique routes to create supramolecular nanostructures at well-defined surfaces. In the present work, we employed scanning tunneling microscopy (STM) in combination with electrochemical techniques to explore the adsorption and phase formation of a series of aromatic carboxylic acids (ACAs) at Au(111)/0.1 M HClO4. Specific goals are to elucidate the roles of electrochemical potential and directional hydrogen-bonding on the structures and orientation of individual ACAs that form nanoarchitectures. ACAs are prototype materials for supramolecular self-assemblies via stereospecific hydrogen bonds between neighboring molecules. In this study, we mainly focus on a special ACA, terephthalic acid (TPA), which is almost insoluble in water, making the assembly of this molecule from aqueous solution challenging. Depending on the applied electric field, TPA molecules form distinctly different, highly ordered adlayers on Au(111) triggered by directional intermolecular hydrogen bonds. At low electrochemical potentials, TPA molecules are planar oriented, forming a potentially infinite hydrogen-bonded adlayer without any observed domain boundaries. The increase of the electrode potential triggers the deprotonation of one carboxylic acid functional group of TPA; additionally, this is accompanied by an orientation change of molecules from planar to perpendicular. In contrast, structural "defects" and multiple domain boundaries were found at this positively charged surface. The assembled nanostructures of TPA are compared with other ACAs (trimesic acid, benzoic acid, and isophthalic acid), and corresponding adsorption models were built for all molecular adlayers, showing that intermolecular hydrogen-bonding plays a determining role in the formation of two-dimensional ACA nanostructures.

Systematic Interaction Analysis of Anti-Human Immunodeficiency Virus Type-1 Neutralizing Antibodies with High Mannose Glycans Using Fragment Molecular Orbital and Molecular Dynamics Methods.

A series of broadly neutralizing antibodies called PGT have been shown to be bound directly to human immunodeficiency virus type-1 via high mannose glycans on glycoprotein gp120. Despite the sequence similarities of amino acids of the antibodies, their affinities to the glycan differ. Glycan-antibody interactions among these antibodies are systematically compared with quantum chemical fragment molecular orbital calculations and molecular dynamics simulations. The differences among structural stability of the glycan in the active site of the complexes and total interaction energies as well as binding free energies between the glycan and antibodies agree well with the experimentally shown affinities of the glycan to the antibodies. The terminal saccharide, Man D3, is structurally stable and responsible for the glycan-antibody binding through electrostatic and dispersion interactions. The structural stability of nonterminal saccharides such as Man 4 or Man C plays substantial roles in the interaction via direct hydrogen bonds. © 2019 Wiley Periodicals, Inc.