scholarly journals Neutron structure of human carbonic anhydrase II in complex with methazolamide: mapping the solvent and hydrogen-bonding patterns of an effective clinical drug

IUCrJ ◽  
2016 ◽  
Vol 3 (5) ◽  
pp. 319-325 ◽  
Author(s):  
Mayank Aggarwal ◽  
Andrey Y. Kovalevsky ◽  
Hector Velazquez ◽  
S. Zoë Fisher ◽  
Jeremy C. Smith ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Active Site ◽  
Room Temperature ◽  
Carbonic Anhydrases ◽  
Structural Comparison ◽  
Methyl Derivative ◽  
X Ray ◽  
Solvent Displacement ◽  
Neutron Structure ◽  
Clinical Drug

Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO2and HCO3−, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with anRcrystof ∼16.0%. Presented in this article, along with only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity (Ki) for both of the drugs against hCA II is similar (∼10 nM). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II–MZM determined at cryotemperature and room temperature. This study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.

scholarly journals Exploring the Structural Chemistry of Pyrophosphoramides: N,N′,N″,N‴-Tetraisopropylpyrophosphoramide

Chemistry ◽  
2021 ◽  
Vol 3 (1) ◽  
pp. 149-163
Author(s):  
Duncan Micallef ◽  
Liana Vella-Zarb ◽  
Ulrich Baisch
Keyword(s):  
Crystal Structure ◽  
Mass Spectrometry ◽  
Nuclear Magnetic Resonance ◽  
Hydrogen Bonding ◽  
Nmr Spectroscopy ◽  
Ir Spectroscopy ◽  
Room Temperature ◽  
Intermolecular Hydrogen Bonding ◽  
X Ray Diffraction ◽  
X Ray

N,N′,N″,N‴-Tetraisopropylpyrophosphoramide 1 is a pyrophosphoramide with documented butyrylcholinesterase inhibition, a property shared with the more widely studied octamethylphosphoramide (Schradan). Unlike Schradan, 1 is a solid at room temperature making it one of a few known pyrophosphoramide solids. The crystal structure of 1 was determined by single-crystal X-ray diffraction and compared with that of other previously described solid pyrophosphoramides. The pyrophosphoramide discussed in this study was synthesised by reacting iso-propyl amine with pyrophosphoryl tetrachloride under anhydrous conditions. A unique supramolecular motif was observed when compared with previously published pyrophosphoramide structures having two different intermolecular hydrogen bonding synthons. Furthermore, the potential of a wider variety of supramolecular structures in which similar pyrophosphoramides can crystallise was recognised. Proton (1H) and Phosphorus 31 (31P) Nuclear Magnetic Resonance (NMR) spectroscopy, infrared (IR) spectroscopy, mass spectrometry (MS) were carried out to complete the analysis of the compound.

Recent insights into lytic polysaccharide monooxygenases (LPMOs)

2018 ◽  
Vol 46 (6) ◽  
pp. 1431-1447 ◽  
Author(s):  
Tobias Tandrup ◽  
Kristian E. H. Frandsen ◽  
Katja S. Johansen ◽  
Jean-Guy Berrin ◽  
Leila Lo Leggio
Keyword(s):  
Active Site ◽  
Room Temperature ◽  
Experimental Studies ◽  
Binding Mode ◽  
Structural Features ◽  
Oxygen Species ◽  
Animal Kingdom ◽  
X Ray ◽  
Lytic Polysaccharide Monooxygenases ◽  
Polysaccharide Monooxygenases

Lytic polysaccharide monooxygenases (LPMOs) are copper enzymes discovered within the last 10 years. By degrading recalcitrant substrates oxidatively, these enzymes are major contributors to the recycling of carbon in nature and are being used in the biorefinery industry. Recently, two new families of LPMOs have been defined and structurally characterized, AA14 and AA15, sharing many of previously found structural features. However, unlike most LPMOs to date, AA14 degrades xylan in the context of complex substrates, while AA15 is particularly interesting because they expand the presence of LPMOs from the predominantly microbial to the animal kingdom. The first two neutron crystallography structures have been determined, which, together with high-resolution room temperature X-ray structures, have putatively identified oxygen species at or near the active site of LPMOs. Many recent computational and experimental studies have also investigated the mechanism of action and substrate-binding mode of LPMOs. Perhaps, the most significant recent advance is the increasing structural and biochemical evidence, suggesting that LPMOs follow different mechanistic pathways with different substrates, co-substrates and reductants, by behaving as monooxygenases or peroxygenases with molecular oxygen or hydrogen peroxide as a co-substrate, respectively.

From a binary salt to salt co-crystals of antibacterial agent lomefloxacin with improved solubility and bioavailability

2015 ◽  
Vol 71 (4) ◽  
pp. 437-446 ◽  
Author(s):  
Zhi-Hui Zhang ◽  
Qi Zhang ◽  
Qing-Qing Zhang ◽  
Chen Chen ◽  
Ming-Yang He ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Barbituric Acid ◽  
Isophthalic Acid ◽  
Water Molecules ◽  
Structural Comparison ◽  
Single Crystal Diffraction ◽  
X Ray ◽  
Enhanced Solubility ◽  
Hydrogen Bonding Networks ◽  
Pharmaceutical Agents

The cocrystallization of lomefloxacin (Lf) with barbituric acid (HBA) and/or isophthalic acid (H2ip) leads to novel binary and ternary saltsviahydrogen-bonding recognition. X-ray single-crystal diffraction analyses show that zwitterionic lomefloxacin can adjust itself to fulfill a different supramolecular array in either binary salts or ternary salt co-crystals, formulated as [HLf]·[Hip]·H2O (1), [HLf]·[BA]·[HBA]·H2O (2) and [HLf]·[BA]·[H2ip]·CH3OH·H2O (3). These pharmaceutical agents present uniform charge-assisted hydrogen-bonding networks between HLf cations and acidic coformers with the lattice capturing water molecules. Structural comparison of (2) and (3) indicated that a delicate balance of geometries and hydrogen-bonding partners is required for stacking to favor the formation of ternary salt co-crystals. Cocrystallization was able to overcome the water insolubility of lomefloxacin. Both the salt co-crystals display enhanced solubility and better pharmaceutical applicability.

scholarly journals Ensemble-based enzyme design can recapitulate the effects of laboratory directed evolution in silico

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Aron Broom ◽  
Rojo V. Rakotoharisoa ◽  
Michael C. Thompson ◽  
Niayesh Zarifi ◽  
Erin Nguyen ◽  
...  
Keyword(s):  
Directed Evolution ◽  
Protein Design ◽  
Active Site ◽  
Room Temperature ◽  
De Novo ◽  
Conformational Ensemble ◽  
Enzyme Design ◽  
X Ray ◽  
Conformational Ensembles ◽  
X Ray Crystallography

Abstract The creation of artificial enzymes is a key objective of computational protein design. Although de novo enzymes have been successfully designed, these exhibit low catalytic efficiencies, requiring directed evolution to improve activity. Here, we use room-temperature X-ray crystallography to study changes in the conformational ensemble during evolution of the designed Kemp eliminase HG3 (kcat/KM 146 M−1s−1). We observe that catalytic residues are increasingly rigidified, the active site becomes better pre-organized, and its entrance is widened. Based on these observations, we engineer HG4, an efficient biocatalyst (kcat/KM 103,000 M−1s−1) containing key first and second-shell mutations found during evolution. HG4 structures reveal that its active site is pre-organized and rigidified for efficient catalysis. Our results show how directed evolution circumvents challenges inherent to enzyme design by shifting conformational ensembles to favor catalytically-productive sub-states, and suggest improvements to the design methodology that incorporate ensemble modeling of crystallographic data.

Polymorphism of naphthazarin and its relation to solid-state proton transfer. Neutron and X-ray diffraction studies on naphthazarin C

1985 ◽  
Vol 399 (1817) ◽  
pp. 295-319 ◽  
Keyword(s):  
Crystal Structure ◽  
Hydrogen Bonding ◽  
Solid State ◽  
Neutron Diffraction ◽  
Room Temperature ◽  
Model Comparison ◽  
Molecular Model ◽  
Molecular Formula ◽  
X Ray Diffraction ◽  
X Ray

The crystal structure of naphthazarin C has been determined by neutron diffraction at 60 and 300 K (λ ═ 0.895 Å; 1 Å ═ 10 -10 m ═ 10 -1 nm) and X-ray diffraction at 300 K. The space group is Pc at 60 K, but P 2 1 /c at 300 K. There are small but significant differences in cell dimensions at the two temperatures: a ═ 7.664 (7.915), b ═ 7.304 (7.262), c ═ 15.16 (15.284) Å; β ═ 114.60 (114.20)°; Z ═ 4; U ═ 771.6 (801.3) Å 3 (values at 300 K in parentheses). Neutron diffraction shows that the Pc and P 2 1 /c structures are related by an order-disorder transition at 110±1 K. Structure analysis (1771 reflections; R F ═ 0.035; R W ═ 0.036) showed that the hydroxyl hydrogens are largely ordered at 60 K, the appropriate molecular formula being 5, 8-dihydroxy-1, 4-naphthadione. Neutron diffraction measurements at 300 K (1769 reflections; R F ═ 0.052) indicated a disordered molecular model with one-half of an hydrogen atom attached to each oxygen. X -ray diffraction measurements on naphthazarin C at 300 K (two independent sets of intensity measurements, one with CuKα and the other with MoKα) support this disordered model. The molecular dimensions for naphthazarin A and B also fit this model. Comparison of the crystal structure of naphthazarin C with those of the A and B polymorphs shows that only the former has intermolecular O─H • • • O hydrogen bonding. The diffraction results combined with the available solid-state n. m. r. data show that there is at room temperature a rapid intramolecular exchange of hydroxylic protons between each pair of oxygen atoms in all three naphthazarin polymorphs. Many 1, 3-diketones exist in an enol form in the solid. These enol forms have been reported to be disordered for about twenty molecules at room temperature (this total includes one molecule studied at 108 K, and four amino-imino systems) and ordered systems have been reported for about fifteen molecules. Intermolecular hydrogen bonding occurs only in a few of these crystals.

Energetic Materials: The Preparation and Structural Characterization of Three Biguanidinium Dinitramides

1997 ◽  
Vol 53 (3) ◽  
pp. 504-512 ◽  
Author(s):  
A. Martin ◽  
A. A. Pinkerton ◽  
R. D. Gilardi ◽  
J. C. Bottaro
Keyword(s):  
Hydrogen Bonding ◽  
Structural Characterization ◽  
Diffraction Data ◽  
Energetic Materials ◽  
Room Temperature ◽  
Asymmetric Structure ◽  
X Ray Diffraction ◽  
X Ray ◽  
Bond Lengths

Three biguanidinium salts of the energetic dinitramide anion have been prepared and structurally characterized from room-temperature X-ray diffraction data. Biguanidinium mono-dinitramide, (BIGH)(DN), triclinic, P\overline 1, a = 4.3686 (4), b = 9.404 (2), c = 10.742 (1) Å, \alpha = 83.54 (1), \beta = 80.386 (9), \gamma = 79.93 (1)°, V = 426.8 (1) Å3, Z = 2, D x = 1.62 g cm−3. Biguanidinium bis-dinitramide, (BIGH2)(DN)2, monoclinic, C2/c, a = 11.892 (2), b = 8.131 (1), c = 13.038 (2) Å, \beta = 115.79 (1)°, V = 1135.1 (3) Å3, Z = 4, D x = 1.84 g cm−3. Biguanidinium bis-dinitramide monohydrate, (BIGH2)(DN)2.H2O, orthorhombic, P212121, a = 6.4201 (6), b = 13.408 (1), c = 14.584 (2) Å, V = 1255.4 (4) Å3, Z = 4, D x = 1.76 g cm−3. All three structures are characterized by extensive hydrogen bonding. Both the mono- and diprotontated cations consist of two planar halves twisted with respect to each other. The dinitramide anion has a surprisingly variable and asymmetric structure. The two halves of the anion are twisted with respect to each other; however, the twist varies from 5.1 to 28.9°. In addition, the two ends of the anion have significantly different geometries, e.g. the `equivalent' N—N bond lengths differ by up to 0.045 Å.

Lewis-Base Adducts of Lead(II) Compounds. X. Synthetic and Structural Studies of Some 1:1 Adducts of 'tet-b' With Lead(II) (Pseudo-)Halides

1996 ◽  
Vol 49 (10) ◽  
pp. 1067 ◽  
Author(s):  
JM Harrowfield ◽  
H Miyamae ◽  
BW Skelton ◽  
AA Soudi ◽  
AH White
Keyword(s):  
Hydrogen Bonding ◽  
Room Temperature ◽  
Lewis Base ◽  
Double Salt ◽  
Rear Side ◽  
Hydrogen Atoms ◽  
X Ray ◽  
Hydrogen Bonding Interactions ◽  
Structure Determinations ◽  
Pseudo Halides

Syntheses and room-temperature single-crystal X-ray structure determinations are recorded for 1 : 1 adducts of (7R*,14R*)-5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane (' tet -b') with a variety of lead(II) salts. [( tet -b)PbCl2] is monoclinic, P 21/c, a 7.183(3), b 12.425(2), c 24.418(2) Ǻ, β 95.32(3)°, Z = 4; conventional R on |F| was 0.044 for 3188 independent, 'observed' (I > 3σ(I)) reflections. [( tet -b)PbI2] is monoclinic, P 21/c, a 19.920(5), b 7.772(5), c 15.605(6) Ǻ, β 108.39(2)°, Z = 4; R 0.051 for No 2507. [( tet -b) Pb (NCS)2] is orthorhombic, P 212121, a 36.99(1), b 8.996(5), c 6.964(3) Ǻ, Z = 4; R 0.043 for No 2100. All are discrete mononuclear [( tet -b)PbX2] entities in which the macrocyclic N4 ligand occupies one 'face' of the N4PbX2 coordination sphere, the thiocyanate ligands being N-bonded, with Pb -N-C angles of 116(2) and 118(1)°; interesting hydrogen-bonding interactions are found, columns of molecules being formed by way of hydrogen bonding between the coordinated (pseudo-)halides and the NH hydrogen atoms which project to the 'rear' face of the ligand of the next molecule, opposite the metal. In contrast to these, the bromide analogue, monoclinic, P21, a 9.342(3), b 12.720(5), c 18.845(5) Ǻ, β 103.17(2)°, Z = 4, R 0.035 for No 3593, is best formulated as [( tet -b) PbBr ] Br, one only of the bromide entities being bound to the lead, the other being fully dissociated by hydrogen bonding/ion pairing to the 'rear' side of adjacent ligands , forming hydrogen-bonded sheets rather than columns. This formulation has been extended to provide a description of an analogous mixed chloride- perchlorate 'double salt', [( tet -b) PbCl ] (ClO4).CH3OH, which is orthorhombic, P 212121, a 19.475(2), b 18.73(1), c 6.820(2) Ǻ, Z = 4, R 0.054 for No 3075. However, another double salt, modelled in refinement as Pb ( tet -b)Cl0.5(ClO4)1.5.H2O, orthorhombic Pnma , a 20.640(5), b 26.16(1), c 8.937(4) Ǻ, Z = 4 dimers , R 0.074 for No 1769, is in this case more appropriately described as [( tet -b) Pb (OClO2O)2Pb( tet -b)] (ClO4) Cl.H2O with perchlorate rather than halide coordinated, and an incipiently dimeric cation, as in the parent [( tet -b) Pb (OClO3)]2 (ClO4)2.2H2O.

Dehydration Time Dependence on Piezoelectric and Mechanical Properties of Bovine Cornea

1999 ◽  
Vol 600 ◽  
Author(s):  
A. C. Jayasuriya ◽  
J. I. Scheinbeim ◽  
V. Lubkin ◽  
G. Bennett ◽  
P. Kramer
Keyword(s):  
Mechanical Properties ◽  
Hydrogen Bonding ◽  
Fourier Transform ◽  
Room Temperature ◽  
Piezoelectric Coefficient ◽  
Water Molecules ◽  
Wide Angle ◽  
X Ray ◽  
Mechanical Responses ◽  
Infra Red

AbstractThe Young's Modulus (E) and piezoelectric coefficient (d31) have been investigated as a function of dehydration time for bovine cornea at room temperature. The piezoelectric and mechanical responses observed were anisotropic for bovine cornea and d31 decreased, while E increased with dehydration. In addition, water molecules appear to increase the crystallinity (of collagen) in the cornea. With dehydration of the cornea, reduction of crystallinity and changes in hydrogen bonding were observed by Fourier Transform Infra Red (FTIR) and Wide Angle X-ray Diffracion (WAXD) measurements.

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