Non-covalent interactions – QTAIM and NBO analysis

MP2(full)/6-311++G(3df,3pd) calculations were carried out on complexes linked through various non-covalent Lewis acid – Lewis base interactions. These are: hydrogen bond, dihydrogen bond, hydride bond and halogen bond. The quantum theory of ´atoms in molecules´ (QTAIM) as well as the natural bond orbitals (NBO) method were applied to analyze properties of these interactions. It was found that for the A-H…B hydrogen bond as well as for the A-X…B halogen bond (X designates halogen) the complex formation leads to the increase of s-character in the A-atom hybrid orbital aimed toward the H or X atom. In opposite, for the A…H-B hydride bond, where the H-atom possesses negative charge, the decrease of s-character in the B-atom orbital is observed. All these changes connected with the redistribution of the electron charge being the effect of the complex formation are in line with Bent´s rule. The numerous correlations between energetic, geometrical, NBO and QTAIM parameters were also found.

Trans-substitution of the proximal hydrogen bond in myoglobin: I. Structural consequences of hydrogen bond deletion

The structural role of a side-chain to side-chain protein hydrogen bond is examined using trans-substitution of the proximal histidine of myoglobin with methylimidazoles (Barrick, Biochemistry 1994;33:6546-6554). Modification of the chemical structure of exogenous ligands allows this hydrogen bond to be disrupted. Comparison of the crystal structures of H93G myoglobin complexed 4-methylimidazole (4meimd; methylation at carbon 4) and 1-methylimidazole (1meimd; methylation at the adjacent nitrogen, preventing hydrogen bonding between the imidazole ligand and the protein) shows that the polypeptide, heme, and methylimidazole orientations are the same within error. For 4meimd there appear to be major and minor conformations corresponding to different tautomeric states of the ligand. Conformational heterogeneity is also seen in the hyperfine-shifted region of the NMR spectrum of 4meimd complexed with high-spin H93G deoxyMb. The major conformation of the 4meimd ligand and the 1meimd ligand, as seen in the respective crystal structures, are quite similar except that the proximal ligand NH-to-Ser92-OH hydrogen bond is eliminated in the 1meimd complex, and instead the proximal ligand CH is adjacent to the Ser92-OH. Thus, this system provides a means to eliminate the Mb proximal hydrogen bond in a chemically and structurally conservative way.     

1-(3-Deoxy-3-fluoro-β-d-glucopyranosyl) pyrimidine derivatives as inhibitors of glycogen phosphorylase b: Kinetic,crystallographic and modelling studies

Design of inhibitors of glycogen phosphorylase (GP) with pharmaceutical applications in improving glycaemic control in type 2 diabetes is a promising therapeutic strategy. The catalytic site of muscle glycogen phosphorylase b (GPb) has been probed with five deoxy-fluro-glucose derivatives. These inhibitors had fluorine instead of hydroxyl at the 3′ position of the glucose moiety and a variety of pyrimidine derivatives at the 1′ position. The best of this carbohydrate-based family of five inhibitors displays a K_i value of 46 μM. To elucidate the mechanism of inhibition for these compounds, the crystal structures of GPb in complex with each ligand were determined and refined to high resolution. The structures demonstrated that the inhibitors bind preferentially at the catalytic site and promote the less active T state conformation of the enzyme by making several favorable contacts with residues of the 280s loop. Fluorine is engaged in hydrogen bond interactions but does not improve glucose potency. The pyrimidine groups are located between residues 284–286 of the 280s loop, Ala383 of the 380s loop, and His341 of the β-pocket. These interactions appear important in stabilizing the inactive quaternary T state of the enzyme. As a follow up to recent computations performed on β-d-glucose pyrimidine derivatives, tautomeric forms of ligands 1–5 were considered as potential binding states. Using Glide-XP docking and QM/MM calculations, the ligands 2 and 5 are predicted to bind in different tautomeric states in their respective GPb complexes. Also, using α-d-glucose as a benchmark model, a series of substitutions for glucose –OH at the 3′ (equatorial) position were investigated for their potential to improve the binding affinity of glucose-based GPb catalytic site inhibitors. Glide-XP and quantum mechanics polarized ligand (QPLD-SP/XP) docking calculations revealed favorable binding at this position to be dominated by hydrogen bond contributions; none of the substitutions (including fluorine) out-performed the native –OH substituent which can act both as hydrogen bond donor and acceptor. The structural analyses of these compounds can be exploited towards the development of better inhibitors.     

Ligand-based and structure-based approaches in identifying ideal pharmacophore against c-Jun N-terminal kinase-3

Structure and ligand based pharmacophore modeling and docking studies carried out using diversified set of c-Jun N-terminal kinase-3 (JNK3) inhibitors are presented in this paper. Ligand based pharmacophore model (LBPM) was developed for 106 inhibitors of JNK3 using a training set of 21 compounds to reveal structural and chemical features necessary for these molecules to inhibit JNK3. Hypo1 consisted of two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), and a hydrophobic (HY) feature with a correlation coefficient (r²) of 0.950. This pharmacophore model was validated using test set containing 85 inhibitors and had a good r² of 0.846. All the molecules were docked using Glide software and interestingly, all the docked conformations showed hydrogen bond interactions with important hinge region amino acids (Gln155 and Met149) and these interactions were compared with Hypo1 features. The results of ligand based pharmacophore model (LBPM) and docking studies are validated each other. The structure based pharmacophore model (SBPM) studies have identified additional features, two hydrogen bond donors and one hydrogen bond acceptor. The combination of these methodologies is useful in designing ideal pharmacophore which provides a powerful tool for the discovery of novel and selective JNK3 inhibitors.     

Metal complexes of virus inhibitors. Part III. Coordination properties of 1-n-propyl-2-α-hydroxybenzylbenzimidazole and the X-ray crystal structure of Ni(C17H18N2O)2(C17H17N2O)1(ClO4)1

Complexes are described of Cobalt(II) and Nickel- (II) salts with the title ligand L. The X-ray crystal structure is described of NiL₂L′₁(ClO₄)₁. One ligand molecule (L′) in this complex is deprotonated and the structure involves strongly hydrogen bonded dimers with OHO bonds = 2.56 Å and 2.62 Å and a NiNi bond = 4.77 Å. The corresponding Cobalt complex is thought to be similar but no other compounds containing L′ were obtained.     

One-pot synthesis of a new 2-substituted 1,2,3-triazole 1-oxide derivative from dipyridyl ketone and isonitrosoacetophenone hydrazone: Nickel(II) complex,DNA binding and cleavage properties

An efficient and simple one-pot synthesis of a new 1,2,3-triazole-1-oxide via reaction between isonitrosoacetophenone hydrazone and dipyridyl ketone in the EtOH/AcOH at room temperature has been developed smoothly in high yield. The reaction proceeds via metal salt free, in-situ formation of asymmetric azine followed by cyclization to provide 1,2,3-triazole 1-oxide compound. It has been structurally characterized. The 1:1 ratio reaction of the 1,2,3-triazole 1-oxide ligand with nickel(II) chloride gives the mononuclear complex [Ni(L)(DMF)Cl₂], hexa-coordinated within an octahedral geometry. Characterization of the 1,2,3-triazole compound and its Ni(II) complex with FTIR, ¹H and ¹³C NMR, UV–vis and elemental analysis also confirms the proposed structures of the compounds. The interactions of the compounds with Calf thymus DNA (CT-DNA) have been investigated by UV–visible spectra and viscosity measurements. The results suggested that both ligand and Ni(II) complex bind to DNA in electrostatic interaction and/or groove binding, also with a slight partial intercalation in the case of ligand. DNA cleavage experiments have been also investigated by agarose gel electrophoresis in the presence and absence of an oxidative agent (H₂O₂). Both 1,2,3-triazole 1-oxide ligand and its nickel(II) complex show nuclease activity in the presence of hydrogen peroxide. DNA binding and cleavage affinities of the 1,2,3-triazole 1-oxide ligand is stronger than that of the Ni(II) complex.     

Effect of solvent environment on the CO band position in the infrared spectrum of trans-[Fe(CN)4(CO)2]

Density functional theory (DFT) is used to understand the effect of hydrogen bonding solvents on the CO band position in the infrared (IR) spectrum of a mono-iron complex, trans-[Fe^II(CN)₄(CO)₂]²⁻. This mono-iron complex has received much attention recently due its potential relation to the biosynthesis of Fe-only hydrogenase enzymes. Our calculations show that the polar solvent molecules preferentially hydrogen bond to the cyano ligands in this complex. The effect of such hydrogen bonding on the electron density distribution is analyzed in terms of the population in natural bond orbitals (NBO). Our results show that the presence of hydrogen bonding to the cyano ligands decreases the extent of back bonding from the metal to the carbonyl ligand. This results in decreased electron density in the π^∗ orbitals of the carbonyl bond leading to a strengthening of the CO bond and a consequent blue shift in the IR band position of the carbonyl group. We also show that the extent of blue shift correlates with the number of nearest neighbor solvent molecules.     

Multiple roles of mobile active center loops in the E1 component of the Escherichia coli pyruvate dehydrogenase complex—Linkage of protein dynamics to catalysis

The region encompassing residues 401–413 on the E1 component of the pyruvate dehydrogenase multienzyme complex from Escherichia coli comprises a loop (the inner loop) which was not seen in the X-ray structure in the presence of thiamin diphosphate, the required cofactor for the enzyme. This loop is seen in the presence of a stable analogue of the pre-decarboxylation intermediate, the covalent adduct between the substrate analogue methyl acetylphosphonate and thiamin diphosphate, C2α-phosphonolactylthiamin diphosphate. It has been shown that the residue H407 and several other residues on this loop are required to reduce the mobility of the loop so electron density corresponding to it can be seen once the pre-decarboxylation intermediate is formed. Concomitantly, the loop encompassing residues 541–557 (the outer loop) appears to work in tandem with the inner loop and there is a hydrogen bond between the two loops ensuring their correlated motion. The inner loop was shown to: (a) sequester the active center from carboligase side reactions; (b) assist the interaction between the E1 and the E2 components, thereby affecting the overall reaction rate of the entire multienzyme complex; (c) control substrate access to the active center. Using viscosity effects on kinetics it was shown that formation of the pre-decarboxylation intermediate is specifically affected by loop movement. A cysteine-less variant was created for the E1 component, onto which cysteines were substituted at selected loop positions. Introducing an electron spin resonance spin label and an ¹⁹F NMR label onto these engineered cysteines, the loop mobility was examined: (a) both methods suggested that in the absence of ligand, the loop exists in two conformations; (b) line-shape analysis of the NMR signal at different temperatures, enabled estimation of the rate constant for loop movement, and this rate constant was found to be of the same order of magnitude as the turnover number for the enzyme under the same conditions. Furthermore, this analysis gave important insights into rate-limiting thermal loop dynamics. Overall, the results suggest that the dynamic properties correlate with catalytic events on the E1 component of the pyruvate dehydrogenase complex.     

Characterization of an Fe<Superscript>III</Superscript>-OOH species and its decomposition product in a bleomycin model system

To model the mononuclear Fe^III-OOH species identified in the catalytic cycle of the anticancer drug bleomycin, the iron chemistry of the pentadentate ligand N-[bis(2-pyridylmethyl)aminoethyl]pyridine-2-carboxamide (H-PaPy₃) has been investigated. The complex [Fe^III(PaPy₃)OCH₃](ClO₄) was reacted with H₂O₂ to form a red species (_max=480 nm, =1800 M^–1 cm^–1) with an S=1/2 EPR signal at g=2.25, 2.17, and 1.95. This species has been identified by electrospray ionization mass spectrometry as [Fe^III(PaPy₃)OOH](ClO₄) and further characterized by resonance Raman and EXAFS analysis. The decomposition of this intermediate leads to the modification of the ligand, as revealed by ¹H NMR. One hydrogen atom is substituted by a solvent-derived methoxy group. The substitution at this site is a result of the two-electron oxidation of the ligand following the heterolytic cleavage of the O–O bond of the Fe^III-OOH species. This is a plausible mechanism to rationalize related ligand modifications that have been proposed in the decay of activated bleomycin.Abbreviations ABLM activated bleomycin - BLM bleomycin - ESI-MS electrospray ionization mass spectrometry - EXAFS extended X-ray absorption fine structure - H-PaPy₃ N-[bis(2-pyridylmethyl)aminoethyl]pyridine-2-carboxamide     

Theoretical investigation on the structure and thermodynamic properties of the 2,4-dinitroimidazole complex with methanol

The structure and thermodynamic properties of the 2, 4-dinitroimidazole complex with methanol were investigated using the B3LYP and MP2(full) methods with the 6-31++G(2d,p) and 6-311++G(3df,2p) basis sets. Four types of hydrogen bonds [N–H?O, C–H?O, O–H?O (nitro oxygen) and O–H?π] were found. The hydrogen-bonded complex having the highest binding energy had a N–H?O hydrogen bond. Analyses of natural bond orbital (NBO) and atoms-in-molecules (AIM) revealed the nature of the intermolecular hydrogen-binding interaction. The changes in thermodynamic properties from monomers to complexes with temperatures ranging from 200.0 to 800.0 K were investigated using the statistical thermodynamic method. Hydrogen-bonded complexes of 2,4-dinitroimidazole with methanol are fostered by low temperatures.

Selective signaling of fluoride anion based on imidazole moieties

The imidazole ring unit in both 2‐(2′‐hydroxyphenyl)‐benzimidazole (ligand a) and a europium(III) complex exhibited specific luminescent responses in the presence of fluoride anions. UV‐visible and ¹H‐nuclear magnetic resonance spectra showed that the NH bond of the imidazole ring can form a hydrogen bond with added fluoride anions. The detection limits are 5 × 10^?6 m for organic ligand and 1.0 × 10^?6 m for the europium complex respectively. The response times are less than 3 s. The europium complex exhibits a linear response in a concentration range lower than 1.0 × 10^?6 m (Y = ?666.86X + 730.1). Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis, characterization, thermal behavior, and DNA-cleaving studies of cyano-bridged nickel(II)-copper(II) complexes of 4-(pyridin-2-ylazenyl)resorcinol

We present here the syntheses of a mononuclear Cu^II complex and two polynuclear Cu^II Ni^II complexes of the azenyl ligand, 4‐(pyridin‐2‐ylazenyl)resorcinol (HL; 1). The reaction of HL ( 1 ) and copper(II) perchlorate with KCN gave a mononuclear complex [CuL(CN)] ( 4 ). Using 4 , one pentanuclear complex, [{CuL(NC)}₄Ni](ClO₄)₂ ( 5 ) and one trinuclear complex, [{CuL(CN)}₂NiL]ClO₄ ( 6 ), were prepared and characterized by elemental analyses, magnetic susceptibility, molar conductance, IR, and thermal analysis. Stoichiometric and spectral results of the mononuclear Cu^II complex indicated that the metal/ligand/CN ratio was 1 : 1 : 1, and the ligand behaved as a tridentate ligand forming neutral metal chelates through the pyridinyl and azenyl N‐, and resorcinol O‐atom. The interaction between the compounds (the ligand 1 , its Ni^II and Cu^II complexes without CN, i.e., 2 and 3 , and its complexes with CN, 4 – 6 ) and DNA has also been investigated by agarose gel electrophoresis. The pentanuclear Cu₄Ni complex ( 5 ) with H₂O₂ as a co‐oxidant exhibited the strongest DNA‐cleaving activity.     

Molecular mechanisms of estrogen recognition and 17-keto reduction by human 17β-hydroxysteroid dehydrogenase 1

The reduction of inactive estrone (E1) to the active estrogen 17β-estradiol (E2) is catalyzed by type 1 17β-hydroxysteroid dehydrogenase (17HSD1). Crystallographic studies, modeling and activity measurement of mutants and chimeric enzymes have led to the understanding of its mechanism of action and the molecular basis for the estrogenic specificity. An electrophilic attack on the C17-keto oxygen by the Tyr 155 hydroxyl is proposed for initiation of the transition state. The active site is a hydrophobic pocket with catalytic residues at one end and the recognition machinery on the other. Tyr 155, Lys 159 and Ser 142 are essential for the activity. The presence of certain other amino acids near the substrate recognition end of the active site including His 152 and Pro 187 is critical to the shape complementarity of estrogenic ligands. His 221 and Glu 282 form hydrogen bonds with 3-hydroxyl of the aromatic A-ring of the ligand. This mechanism of recognition of E1 by 17HSD1 is similar to that of E2 by estrogen receptor α. In a ternary complex with NADP⁺ and equilin, an equine estrogen with C7=C8 double bond, the orientation of C17=O of equilin relative to the C4-hydride is more acute than the near normal approach of the hydride for the substrate. In the apo-enzyme structure, a substrate-entry loop (residues 186–201) is in an open conformation. The loop is closed in this complex and Phe 192 and Met 193 make contacts with the ligand. Residues of the entry loop could be partially responsible for the estrogenic specificity.     

Mimicking the photosynthetic system with strong hydrogen bonds to promote proton electron concerted reactions

A Copper(2+) complex with a Cu^II–C bond containing sp³ configuration was used to investigate the role of strong hydrogen bonds in proton coupled electron transfer (PCET) reactions. The only example of a Cu^II–C system realized so far is that using tris-(pyridylthio)methyl (tptm) as a tetradentate tripodal ligand. Using this ligand, [CuF(tptm)] and [Cu(tptm)(OH)] have been prepared. The former complex forms supra-molecular arrays of layers of the complex between which hydroquinone is intercalated in the crystalline phase. This hydroquinone intercalation crystal was prepared via the photochemical conversion of quinone during the crystallization process. This conversion reaction probably involves a proton coupled electron transfer process. The nuclear magnetic resonance spectroscopic analysis of the reaction mixture shows the presence of Cu(III) during the conversion reaction. These results strongly suggest the presence of the molecular aggregate of the [CuF(tptm)] complex, water and quinone in the solution phase during the quinone to hydroquinone conversion. The presence of this type of aggregate requires a strong hydrogen bond between the [CuF(tptm)] complex and water. The presence of this particular hydrogen bond is a unique character of such a complex that has the Cu^II–C bond. This complex is used as a model for photosynthetic water splitting since the photoconversion of quinone to hydroquinone also involves the production of oxygen from water.     

Coordination modes of N-(2-hydroxyphenyl)methyl-bis-(2-pyridylmethyl)amine with copper (I) and (II) halides

The title ligand, N-(2-hydroxyphenyl)methyl-bis-(2-pyridylmethyl)amine, was prepared via a condensation-reduction synthetic route. The compounds, CuCl(C₁₉H₁₉N₃O) and [CuBr(C₁₉H₁₉N₃O)]⁺Br⁻ · 3H₂O, were readily synthesized from the reaction of CuCl or CuBr₂ and the ligand in acetonitrile. The title copper(I) compound is an O-H ? Cl hydrogen-bonded linear chain of tetrahedrally coordinated copper centers, and the title copper(II) compound exists as two strongly tetragonally distorted dibromide bridged metal cations in a dimer with the phenol hydroxyl groups weakly bound in a trans-fashion to one of the bridging bromides. In the copper(I) complex the phenoxy group acts only as a hydrogen bond donor, whereas in the copper(II) complex it acts both as a ligand and a hydrogen bond donor.     

An unusual cis-phosphonodithioato Pd(II) complex in an extensive hydrogen bonding 3D network

The P-N bond hydrolysis of the 4-methoxyphenyl-ammoniumethylamido-phosphonodithioato ligand on complexation to Pd^II leads to the first example of a Pd-phosphonodithioato complex in a cis configuration, stabilised in the solid state by an extended network of hydrogen bondings involving the released ethylenediamine and a water molecule.     

Thioamide substitution to probe the hydroxyproline recognition of VHL ligands

Thioamide substitution influences hydrogen bond and n → π¹ interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n → π¹ interactions in fine tuning hydroxyproline recognition by VHL.     

Loop–loop interaction in an adenine-sensing riboswitch: A molecular dynamics study

Riboswitches are mRNA-based molecules capable of controlling the expression of genes. They undergo conformational changes upon ligand binding, and as a result, they inhibit or promote the expression of the associated gene. The close connection between structural rearrangement and function makes a detailed knowledge of the molecular interactions an important step to understand the riboswitch mechanism and efficiency. We have performed all-atom molecular dynamics simulations of the adenine-sensing add A-riboswitch to study the breaking of the kissing loop, one key tertiary element in the aptamer structure. We investigated the aptamer domain of the add A-riboswitch in complex with its cognate ligand and in the absence of the ligand. The opening of the hairpins was simulated using umbrella sampling using the distance between two loops as the reaction coordinate. A two-step process was observed in all the simulated systems. First, a general loss of stacking and hydrogen bond interactions is seen. The last interactions that break are the two base pairs G37-C61 and G38-C60, but the break does not affect the energy profile, indicating their pivotal role in the tertiary structure formation but not in the structure stabilization. The junction area is partially organized before the kissing loop formation and residue A24 anchors together the loop helices. Moreover, when the distance between the loops is increased, one of the hairpins showed more flexibility by changing its orientation in the structure, while the other conserved its coaxial arrangement with the rest of the structure.     

Structural insights into ligand binding features of dual FABP4/5 inhibitors by molecular dynamics simulations

Abstract

The fatty acid binding protein (FABP) 4 and 5 have been considered as potential targets for the treatment of metabolic diseases. A compensatory upregulation of FABP5 due to the gene ablation of FABP4 in adipocytes indicated the importance of dual FABP4/5 inhibitors. A few compounds have been discovered as dual FABP4/5 inhibitors. However, none exhibited equivalent inhibitory activity against both FABP4 and FABP5, and almost all compounds showed weaker inhibition against FABP5. To provide a better structural understanding for the design of potent dual FABP4/5 inhibitors, molecular dynamics simulations have been performed for 100?ns to disclose the ligand binding features in FABP4 and FABP5 using Amber14, respectively. Key residues were identified by analysis of close contact, hydrogen bond occupancy, binding free energy and alanine scanning mutagenesis. In addition, induced-fit effects have been observed upon ligand binding in the process of simulations. The shifted alkyl chain of ligand in FABP4 was significantly different from that in FABP5 due to the corresponding residues (Phe58^FABP4 and Leu60^FABP5). Thus, to avoid different steric effects made by these two residues, hydrophobic groups of suitable size should be taken into account. Besides, electrostatic and steric effects with Arg107^FABP4 and Arg109^FABP5 should be paid more attention to. The results will facilitate the rational design of dual FABP4/5 inhibitors.     

Molecular Structure Evaluation of Wheat Gluten during Frozen Storage

The effects of frozen storage (0–120 day) on the secondary structure and molecular chain conformation of hydrated gluten were investigated using Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy (AFM). After frozen storage, no changes were observed in the secondary structure of the 60% hydrated gluten; spectra were consistent with a tight ordered structure with many interchain hydrogen bond interactions. For the dehydrated gluten, more complex changes took place: during frozen storage for up to 60 days, there were distinctive changes in the low-frequency region of the amide I band (1618–1633 cm^?1) which were attributed to changes in the β-sheet structure. However, with the increase of frozen storage from 60 to 120 days, a band near 1614 cm^?1 replaced that at 1659 cm^?1 illustrate that the formation of protein aggregates during the long-time frozen storage, which along with the establishment of new intermolecular non-covalent bonds within the protein molecule or between two neighboring molecules. AFM images showed that the gluten chain formed a fibril-like branched network, and this network was weakened with increasing frozen storage time.