Positions Of Hydrogen Atoms Research Articles

Elucidation of Hydrogen Bonding Patterns in Ligand-Free, Lactose- and Glycerol-Bound Galectin-3C by Neutron Crystallography to Guide Drug Design.

The medically important drug target galectin-3 binds galactose-containing moieties on glycoproteins through an intricate pattern of hydrogen bonds to a largely polar surface-exposed binding site. All successful inhibitors of galectin-3 to date have been based on mono- or disaccharide cores closely resembling natural ligands. A detailed understanding of the H-bonding networks in these natural ligands will provide an improved foundation for the design of novel inhibitors. Neutron crystallography is an ideal technique to reveal the geometry of hydrogen bonds because the positions of hydrogen atoms are directly detected rather than being inferred from the positions of heavier atoms as in X-ray crystallography. We present three neutron crystal structures of the C-terminal carbohydrate recognition domain of galectin-3: the ligand-free form and the complexes with the natural substrate lactose and with glycerol, which mimics important interactions made by lactose. The neutron crystal structures reveal unambiguously the exquisite fine-tuning of the hydrogen bonding pattern in the binding site to the natural disaccharide ligand. The ligand-free structure shows that most of these hydrogen bonds are preserved even when the polar groups of the ligand are replaced by water molecules. The protonation states of all histidine residues in the protein are also revealed and correlate well with NMR observations. The structures give a solid starting point for molecular dynamics simulations and computational estimates of ligand binding affinity that will inform future drug design.

Red/Green Color Tuning of Visual Rhodopsins: Electrostatic Theory Provides a Quantitative Explanation

We present a structure-based theory of the long-wavelength (red/green) color tuning in visual rhodopsins and its application to the analysis of site-directed mutagenesis experiments. Using a combination of electrostatic and molecular-mechanics methods, we explain the measured mutant-minus-wild-type absorption shifts and conclude that the dominant mechanism of the color tuning in these systems is electrostatic pigment-protein coupling. An important element of our analysis is the independent determination of protonation states of titratable residues in the wild type and the mutant protein as well as the self-consistent reoptimization of hydrogen atom positions, which includes the relaxation of the hydrogen bonding network and the reorientation of water molecules. On the basis of this analysis, we propose a "dipole-orientation rule" according to which both the position and the orientation of a polar group introduced in the protein environment determine the direction of the transition energy shift of the retinal chromophore.

Neutron Crystallography Detects Differences in Protein Dynamics: Structure of the PKG II Cyclic Nucleotide Binding Domain in Complex with an Activator

As one of the main receptors of a second messenger, cGMP, cGMP-dependent protein kinase (PKG) isoforms I and II regulate distinct physiological processes. The design of isoform-specific activators is thus of great biomedical importance and requires detailed structural information about PKG isoforms bound with activators, including accurate positions of hydrogen atoms and a description of the hydrogen bonding and water architecture. Here, we determined a 2.2 Å room-temperature joint X-ray/neutron (XN) structure of the human PKG II carboxyl cyclic nucleotide binding (CNB-B) domain bound with a potent PKG II activator, 8-pCPT-cGMP. The XN structure directly visualizes intermolecular interactions and reveals changes in hydrogen bonding patterns upon comparison to the X-ray structure determined at cryo-temperatures. Comparative analysis of the backbone hydrogen/deuterium exchange patterns in PKG II:8-pCPT-cGMP and previously reported PKG Iβ:cGMP XN structures suggests that the ability of these agonists to activate PKG is related to how effectively they quench dynamics of the cyclic nucleotide binding pocket and the surrounding regions.

Adsorption, hydrogenation and dehydrogenation of C2H on a CoCu bimetallic layer

In this paper, adsorption, hydrogenation and dehydrogenation of C2H on a single atomic layer of bimetallic CoCu were investigated using first-principles calculations. The CoCu bimetallic layer is formed by Cu replacement of partial Co atoms on the top layer of a Co(111) surface. Our adsorption and reaction results showed those sites, which have stronger adsorption energy of C2H, possess higher reactivity. The bimetallic layer possesses higher reactivity than either of the pure monometallic layer. A mechanism of higher reactivity of the bimetallic layer is proposed and identified, i.e. in the bimetallic catalyst, the catalytic performance of one component is promoted by the second component, and in our work, the catalytic performance of Co atoms in the bimetallic layer are improved by introducing Cu atoms, lowing the activation barrier of the reaction of C2H. The bimetallic layer could tune adsorption and reaction of C2H by modulating the ratio of Co and Cu. Results of adsorption energies and adsorption configurations reveal that C2H prefers to be adsorbed in parallel on both the pure Co metallic and CoCu bimetallic layers, and Co atoms in subsurface which support the metallic or bimetallic layer have little effect on C2H adsorption. For hydrogenation reactions, the products greatly depend on the concentration and initial positions of hydrogen atoms, and the C2H hydrogenation forming acetylene is more favorable than forming vinylidene in both thermodynamics and kinetics. This study would provide fundamental guidance for hydrocarbon reactions on Co-based and/or Cu-based bimetallic surface chemistry and for development of new bimetallic catalysts.

Isomerization of Hydrofluorocyclopentenes Promoted by Fluoride Anion

The isomerization of hydrofluorocyclopentenes promoted by fluoride anion was investigated. It was found that two processes were responsible for interconversion of the isomers: an allylic syn-addition/elimination of fluoride anion that does not change the mutual positions of hydrogen atoms but is responsible for transfers of fluorine atoms, and a fluoride anion-assisted deprotonation/protonation which does not change the mutual positions of fluorine atoms but is responsible for transfers of hydrogen atoms. In the deprotonation, HF can easily capture excess fluoride anion to form HF2- anion which can probably inhibit the protonation.

Engineering Codrug Solid Forms: Mechanochemical Synthesis of an Indomethacin–Caffeine System

This article reports on the preparation and solid-state characterization of an indomethacin–caffeine drug–drug cocrystal (or codrug) in a 1:1 stoichiometry. These two active ingredients are frequently coadministered as part of a therapy against strong migraines, in a commercially available fixed dose combination formulation. The X-ray crystal structure of the codrug is characterized by a hydrogen bond interaction between the carboxylic moiety of indomethacin and the purinic nitrogen atom of caffeine. The combination of multinuclear and multidimensional solid-state NMR measurements (1H MAS, 13C and 15N CPMAS, 1H DQ MAS, 13C–1H HETCOR, 14N–1H J- and D-HMQC), as well as IR data, provided spectroscopic evidence about the hydrogen atom position along the hydrogen bond axis, thereby confirming the neutral nature of the cocrystal. Furthermore, dissolution kinetic tests revealed superior bioavailability of indomethacin in the codrug compared to indomethacin alone and to an indomethacin–caffeine physical mixture. ...

Direct visualization of critical hydrogen atoms in a pyridoxal 5\u2032-phosphate enzyme

Enzymes dependent on pyridoxal 5′-phosphate (PLP, the active form of vitamin B6) perform a myriad of diverse chemical transformations. They promote various reactions by modulating the electronic states of PLP through weak interactions in the active site. Neutron crystallography has the unique ability of visualizing the nuclear positions of hydrogen atoms in macromolecules. Here we present a room-temperature neutron structure of a homodimeric PLP-dependent enzyme, aspartate aminotransferase, which was reacted in situ with α-methylaspartate. In one monomer, the PLP remained as an internal aldimine with a deprotonated Schiff base. In the second monomer, the external aldimine formed with the substrate analog. We observe a deuterium equidistant between the Schiff base and the C-terminal carboxylate of the substrate, a position indicative of a low-barrier hydrogen bond. Quantum chemical calculations and a low-pH room-temperature X-ray structure provide insight into the physical phenomena that control the electronic modulation in aspartate aminotransferase.

Tautomerism in acyl-pyrazolones and in a novel photolysis product—importance and impact of the accurate localization of hydrogen atoms in crystal structures

Acyl-pyrazolones exist in four different tautomeric forms (two keto and two enol) in crystal structures. Routine crystal structure refinements using an independent atom model and routine isolated-molecule calculations fail in locating the mobile hydrogen atoms accurately in 22 investigated acyl-pyrazolone examples. However, a combination of both within the framework of quantum crystallography represented by the method of Hirshfeld atom refinement accurately locates the mobile hydrogen atom in a resonance-assisted hydrogen bond of title compound 3, a novel photolysis product. The impact of the hydrogen atom position on the resonance system of the non-hydrogen framework of the various tautomers is discussed, and the importance of intermolecular interactions for the positioning of the hydrogen atom is highlighted.

Ewald: an extended wide-angle Laue diffractometer for the second target station of the Spallation Neutron Source.

Visualizing hydrogen atoms in biological materials is one of the biggest remaining challenges in biophysical analysis. While X-ray techniques have unrivaled capacity for high-throughput structure determination, neutron diffraction is uniquely sensitive to hydrogen atom positions in crystals of biological materials and can provide a more complete picture of the atomic and electronic structures of biological macromolecules. This information can be essential in providing predictive understanding and engineering control of key biological processes, for example, in catalysis, ligand binding and light harvesting, and to guide bioengineering of enzymes and drug design. One very common and large capability gap for all neutron atomic resolution single-crystal diffractometers is the weak flux of available neutron beams, which results in limited signal-to-noise ratios giving a requirement for sample volumes of at least 0.1 mm3. The ability to operate on crystals an order of magnitude smaller (0.01 mm3) will open up new and more complex systems to studies with neutrons which will help in our understanding of enzyme mechanisms and enable us to improve drugs against multi resistant bacteria. With this is mind, an extended wide-angle Laue diffractometer, 'Ewald', has been designed, which can collect data using crystal volumes below 0.01 mm3.

Predicting the Position of the Hydrogen Atom in the Short Intramolecular Hydrogen Bond of the Hydrogen Maleate Anion from Geometric Correlations

The position of the hydrogen atom inside the strong and short intramolecular hydrogen bond of the hydrogen maleate anion strongly varies depending on the crystalline environment. Therefore, it has not been possible in the past to accurately determine it using X-ray diffraction data although there are 292 hydrogen maleate crystal structures with different cations in the literature. In this study, a geometric correlation for the accurate prediction of the hydrogen position in the short intramolecular hydrogen bond is presented. The results used to derive the correlation are obtained from low-temperature neutron-diffraction studies on nine different hydrogen maleate salts that span the whole range from perfectly symmetric to highly asymmetric intramolecular hydrogen bonds. Since the only variable in the correlation as derived from the neutron data is the O···O distance, the hydrogen atom position in question can subsequently be predicted using information that is accurately available from routine X-ray data....

Should we remediate small-molecule structures? If so, who should do it?

ABSTRACTProblems can arise in crystallographic databases with errors and omissions in the representation of data that impede searches, and with errors in the actual data. While the Cambridge Crystallographic Data Centre with its Improvement Projects has solved many of the first category of problems, errors in atomic coordinates and other crystallographic data are surprisingly common. Although modern software warns of many types of error, such errors appear even in recently deposited Crystallographic Information Files. Richard Marsh found many examples of missed symmetry in assignment of the space group; such errors are now waning. Hydrogen atoms are commonly placed in calculated positions. Particularly for OH and NH groups involved in hydrogen bonds, occupancy factors may need to be reduced to 0.5 or the hydrogen atom positions may require amendment. Examples of acids and imidazole derivatives are provided, showing that sometimes only consideration of bond distances and angles at the heteroatom can distin...

Raman spectroscopy and theoretic study of hyperpolarizability effect in diiodobutenyl‐bis‐thioquinolinium triiodide at low temperature

Various structural features, such as proton disorder or noncovalent interactions, determine the existence of switchable nonlinear optical properties under varying external conditions. Thus, for the single crystal of diiodobutenyl‐bis‐thioquinolinium triiodide with the bridge hydrogen atom, previously characterized under ambient conditions by C2/c symmetry, we have measured Raman spectra in the temperature range from 298 K down to 113 K. Variations in low‐wavenumber region of Raman spectra at temperatures below 153 K have been attributed to the change of the bridge hydrogen atom position in the [NHN]+ fragment, thus lowering the crystal symmetry from C2/c to Cc. Quantum chemical calculations in the solid state for noncentrosymmetric Cc structure predict high hyperpolarizability and second‐order electric susceptibilities, comparable to those of modern nonlinear optical materials. This indicates the emergence of nonlinear optical properties in the low‐temperature phase of the studied crystal. Copyright © 2017 John Wiley & Sons, Ltd.

Structural and Vibrational Characterization of the Chromophore Binding Site of Bacterial Phytochrome Agp1.

Agp1 is a prototypical bacterial phytochrome from Agrobacterium fabrum harboring a biliverdin cofactor which reversibly photoconverts between a red-light-absorbing (Pr) and a far-red-light-absorbing (Pfr) states. The reaction mechanism involves the isomerization of the bilin-chromophore followed by large structural changes of the protein matrix that are coupled to protonation dynamics at the chromophore binding site. Histidines His250 and His280 participate in this process. Although the three-dimensional structure of Agp1 has been solved at high resolution, the precise position of hydrogen atoms and protonation pattern in the chromophore binding pocket has not been investigated yet. Here, we present protonated structure models of Agp1 in the Pr state involving appropriately placed hydrogen atoms that were generated by hybrid quantum mechanics/molecular mechanics- and electrostatic calculations and validated against experimental structural- and spectroscopic data. Although the effect of histidine protonation on the vibrational spectra is weak, our results favor charge neutral H250 and H280 both protonated at Nε. However, a neutral H250 with a proton at Nε and a cationic H280 may also be possible. Furthermore, the present QM/MM calculations of IR and Raman spectra of Agp1 containing isotope-labeled BV provide a detailed vibrational assignment of the biliverdin modes in the fingerprint region.

Insights into the Catalytic Mechanism and Transition State Stabilization of 5′‐Methylthioadenosine Nucleosidase using Neutron Crystallography

5′‐Methylthioadenosine nucleosidase (MTAN) is an obligatory homodimeric protein that catalyzes the hydrolysis of the N‐ribosidic bond of a variety of adenosine‐containing metabolites. The proposed catalytic mechanism of MTAN is initiated by D198 protonating the N7 position of the adenyl moiety, which consequently causes elongation and ultimate breaking of the N‐ribosidic bond, resulting in the formation of an oxocarbenium ion intermediate. Of particular interest is the pKa elevation of D198 that was proposed to have a value of 8.2, which is significantly higher than the theoretical pKa for an aspartic acid side chain. In this study we present the first joint X‐ray/neutron crystal structures of Helicobacter pylori MTAN (HpMTAN) in complex with a substrate (S‐adenosylhomocysteine), early (Formycin A) and late (p‐ClPh‐Thio‐DADMe‐ImmA) dissociative transition state analogues, as well as with the catalytic products (adenine and S‐ribosylhomocysteine). The solved X‐ray/neutron crystal structures provide the positions of exchangeable hydrogen atoms and protonation states of ionizable groups that further our understanding of the catalytic mechanism as well as the stabilization of the transition state for HpMTAN. These results confirm that the catalytic reaction is initiated by D198 functioning as a general acid through the observation of a shared deuterium atom with unconventional hydrogen bond geometry between the carboxylate group of D198 and the N7 position of adenine. Additionally, the transition state analogues neutron structures illustrate the minor differences in the hydrogen bond interactions resulting in the DADMe‐ImmA analogues being extremely potent inhibitors with Kd values in the picomolar range, despite HpMTAN shown to contain an early dissociative transition state structure.Support or Funding InformationThis work was supported by the Center for the Advancement of Science in Space via a cooperative agreement with National Aeronautics and Space Administration Grant N‐123528‐01 (to D.R.R) and by National Institute of Allergy and Infectious Disease/NIH Grant AI105084 (to D.R.R.).

Hydrogen Atomic Positions of O-H···O Hydrogen Bonds in Solution and in the Solid State: The Synergy of Quantum Chemical Calculations with ¹H-NMR Chemical Shifts and X-ray Diffraction Methods.

The exact knowledge of hydrogen atomic positions of O–H···O hydrogen bonds in solution and in the solid state has been a major challenge in structural and physical organic chemistry. The objective of this review article is to summarize recent developments in the refinement of labile hydrogen positions with the use of: (i) density functional theory (DFT) calculations after a structure has been determined by X-ray from single crystals or from powders; (ii) 1H-NMR chemical shifts as constraints in DFT calculations, and (iii) use of root-mean-square deviation between experimentally determined and DFT calculated 1H-NMR chemical shifts considering the great sensitivity of 1H-NMR shielding to hydrogen bonding properties.

Hydrogen positions in single nanocrystals revealed by electron diffraction.

The localization of hydrogen atoms is an essential part of crystal structure analysis, but it is difficult because of their small scattering power. We report the direct localization of hydrogen atoms in nanocrystalline materials, achieved using the recently developed approach of dynamical refinement of precession electron diffraction tomography data. We used this method to locate hydrogen atoms in both an organic (paracetamol) and an inorganic (framework cobalt aluminophosphate) material. The results demonstrate that the technique can reliably reveal fine structural details, including the positions of hydrogen atoms in single crystals with micro- to nanosized dimensions.

Electron diffraction and the hydrogen atom.

Dynamical refinement with electron-diffraction data reveals hydrogen atom positions

Crystal structure, hydrogen absorption-desorption behavior and magnetic properties of the Nd3−xMgxCo9 alloys

New Nd3−xMgxCo9 alloys have been synthesized by powder sintering method and their crystal structure, hydrogen storage and magnetic properties have been systematically studied. X-ray diffraction analysis showed that Nd3−xMgxCo9 (x ≤ 1.5) alloys belong to the PuNi3-type structure and NdMg2Co9 is an individual ternary compound with YIn2Ni9-type structure. Hydrogen storage capacity of the PuNi3-type Nd3−xMgxCo9 alloys is in the range 1.1–1.6 wt % H at room temperature, while for NdMg2Co9 it is below 0.5 wt % H. PСT measurements demonstrated that thermodynamic stability of hydrides decrease with increasing Mg content. Hydrides of the alloys with lower Mg content (x ≤ 1.0) are stable in air at room temperature. XRD study of these hydrides showed preserved PuNi3-type structure with hydrogen-induced volume expansion 16.7–24%. The positions of hydrogen atoms were determined by neutron powder diffraction study of Nd2MgCo9D10. In the Nd2MgCo9D10 structure D atoms partially occupy four types of interstices, including octahedral Nd2Co4 sites, tetrahedral Nd2Co2 sites and two types of trigonal bipyramids (Nd,Mg)3Co2. Electrochemical investigations of the Nd2MgCo9 electrode demonstrated rather low discharge capacity, 100 mAh/g, which is about 30% of its theoretical capacity. Magnetic measurements have shown that Nd2MgCo9 is ferromagnetic with high Curie temperature (TC = 633 K) and spin reorientation at 225 K, its hydrogenation causes a significant decrease of the magnetization.

Hydrogen maleate salts: precise and accurate determination of the hydrogen atom position in short hydrogen bonds using X-ray diffraction at extremely low temperatures

Hydrogen maleate salts: precise and accurate determination of the hydrogen atom position in short hydrogen bonds using X-ray diffraction at extremely low temperatures

Structural insights into the thermal decomposition sequence of barium tetrahydrogenorthotellurate(VI), Ba[H4TeO6

The compounds Ba[H4TeO6] (I), Ba[H2TeO5] (II), Ba[Te2O6(OH)2] (III) and Ba[TeO4] (IV) were prepared by application of a diffusion method (I), under hydrothermal conditions (II and III) and from solid state reactions (IV), respectively. Structure analysis on the basis of single crystal X-ray diffraction data revealed novel structure types for (I), (II) and (III) and isotypism of (IV) with PrSbO4 and LaSbO4. Common feature of the four oxotellurate(VI) structures are [TeO6] octahedra. Whereas in the crystal structure of (I) the octahedral units are isolated, they are condensed into chains via corner-sharing in (II) and via edge-sharing in (III) and (IV). The coordination numbers of the barium cations in the four structures range from seven to ten. Although hydrogen atom positions could not be located for the structures of (I) and (II), short interpolyhedral O···O contacts are evident for strong hydrogen bonding. The temperature behaviour of (I), (II) and (IV) was monitored by simultaneous thermal analysis (STA) measurements and in situ powder X-ray diffraction, revealing the decomposition sequence Ba[H4TeO6] → Ba[H2TeO5] → Ba[TeO4]→ Ba[TeO3] upon heating to temperatures up to 900°C.