scholarly journals Charge density studies of interactions in macromolecules – the case of sunitinib

2014 ◽  
Vol 70 (a1) ◽  
pp. C970-C970
Author(s):  
Maura Malińska ◽  
Katarzyna Jarzembska ◽  
Anna Goral ◽  
Andrzej Kutner ◽  
Krzysztof Woźniak ◽  
...  
Keyword(s):  
Charge Density ◽  
Interaction Energy ◽  
Electron Density ◽  
Electrostatic Interaction ◽  
Tyrosine Kinases ◽  
Electrostatic Interactions ◽  
Kinase Inhibitor ◽  
Topological Analysis ◽  
3D Structure ◽  
X Ray

Electron density is a key factor in determining properties of molecules. Knowledge of the electron density distribution allows to determine not only the 3D structure of molecules, but also various one-electron properties (electric moments, electrostatic potential, electrostatic interaction energy, etc.). X-ray diffraction is a great tool for obtaining this kind of information. For macromolecules, however, quantitative determination of charge density from experiment is possible on rare occasions only. We will present that with the University at Buffalo pseudoatom database (UBDB) approach [1,2] it is now possible to reconstruct electron density of any macromolecular system for which atomic coordinates are available. The approach is fast and opens an excellent opportunity to investigate macromolecular complexes by means of topological analysis of electron density (and derivatives thereof), electrostatic interaction energy analysis, and many others. The results of our studies on sunitinib (SU) will illustrate the possibilities of the approach. SU is an inhibitor of tyrosine kinases and was approved as a drug in 2006. Comprehensive analysis of the SU malate crystal and SU complexes with a series of protein kinases was carried out. The high resolution single crystal X-ray measurement and UBDB approach served as the basis for the reconstruction of the charge density of SU and the protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the SU malate crystal to that in the protein binding pockets. SU forms nine preserved bond paths corresponding to hydrogen bonds and also to the C-H...O and C-H...π contacts common for all analyzed kinases. It interacts typically with similar electrostatic interaction energy with the studied proteins and can adjust its conformation to fit the binding pocket in a way to enhance the electrostatic interactions. Such behavior can be responsible for a broad spectrum of action of SU as kinase inhibitor.

Molecular tapes in the structure of isoguaninium chloride

2017 ◽  
Vol 74 (1) ◽  
pp. 108-112 ◽  
Author(s):  
Urszula Anna Budniak ◽  
Paulina Maria Dominiak
Keyword(s):  
Crystal Structure ◽  
Single Crystal ◽  
Charge Density ◽  
Interaction Energy ◽  
Electrostatic Interaction ◽  
Electrostatic Interactions ◽  
The Other ◽  
X Ray Diffraction ◽  
X Ray ◽  
Diffraction Structure

Isoguanine, an analogue of guanine, is of intrinsic interest as a noncanonical nucleobase. The crystal structure of isoguaninium chloride (systematic name: 6-amino-2-oxo-1H,7H-purin-3-ium chloride), C5H6N5O+·Cl−, has been determined by single-crystal X-ray diffraction. Structure analysis was supported by electrostatic interaction energy (E es) calculations based on charge density reconstructed with the UBDB databank. In the structure, two kinds of molecular tapes are observed, one parallel to (010) and the other parallel to (50\overline{4}). The tapes are formed by dimers of isoguaninium cations interacting with chloride anions. E es analysis indicates that cations in one kind of tape are oriented so as to minimize repulsive electrostatic interactions.

Sunitinib: from charge-density studies to interaction with proteins

2014 ◽  
Vol 70 (5) ◽  
pp. 1257-1270 ◽  
Author(s):  
Maura Malińska ◽  
Katarzyna N. Jarzembska ◽  
Anna M. Goral ◽  
Andrzej Kutner ◽  
Krzysztof Woźniak ◽  
...  
Keyword(s):  
Hydrogen Bonds ◽  
Charge Density ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Electrostatic Interactions ◽  
Kinase Inhibitor ◽  
Protein Complexes ◽  
Binding Pocket ◽  
Type I ◽  
Sunitinib Malate

Protein kinases are targets for the treatment of a number of diseases. Sunitinib malate is a type I inhibitor of tyrosine kinases and was approved as a drug in 2006. This contribution constitutes the first comprehensive analysis of the crystal structures of sunitinib malate and of complexes of sunitinib with a series of protein kinases. The high-resolution single-crystal X-ray measurement and aspherical atom databank approach served as a basis for reconstruction of the charge-density distribution of sunitinib and its protein complexes. Hirshfeld surface and topological analyses revealed a similar interaction pattern in the sunitinib malate crystal structure to that in the protein binding pockets. Sunitinib forms nine preserved bond paths corresponding to hydrogen bonds and also to the C—H...O and C—H...π contacts common to the VEGRF2, CDK2, G2, KIT and IT kinases. In general, sunitinib interacts with the studied proteins with a similar electrostatic interaction energy and can adjust its conformation to fit the binding pocket in such a way as to enhance the electrostatic interactions,e.g.hydrogen bonds in ligand–kinase complexes. Such behaviour may be responsible for the broad spectrum of action of sunitinib as a kinase inhibitor.

Revisiting the charge density analysis of 2,5-dichloro-1,4-benzoquinone at 20 K

2017 ◽  
Vol 73 (4) ◽  
pp. 654-659 ◽  
Author(s):  
Zhijie Chua ◽  
Bartosz Zarychta ◽  
Christopher G. Gianopoulos ◽  
Vladimir V. Zhurov ◽  
A. Alan Pinkerton
Keyword(s):  
Charge Density ◽  
Electron Density ◽  
Topological Analysis ◽  
Diffraction Measurement ◽  
X Ray Diffraction ◽  
Total Electron Density ◽  
Total Electron ◽  
Structure Factors ◽  
Density Analysis ◽  
Experimental Charge Density

A high-resolution X-ray diffraction measurement of 2,5-dichloro-1,4-benzoquinone (DCBQ) at 20 K was carried out. The experimental charge density was modeled using the Hansen–Coppens multipolar expansion and the topology of the electron density was analyzed in terms of the quantum theory of atoms in molecules (QTAIM). Two different multipole models, predominantly differentiated by the treatment of the chlorine atom, were obtained. The experimental results have been compared to theoretical results in the form of a multipolar refinement against theoretical structure factors and through direct topological analysis of the electron density obtained from the optimized periodic wavefunction. The similarity of the properties of the total electron density in all cases demonstrates the robustness of the Hansen–Coppens formalism. All intra- and intermolecular interactions have been characterized.

scholarly journals Topology of the Electron Density and of Its Laplacian from Periodic LCAO Calculations on f-Electron Materials: The Case of Cesium Uranyl Chloride

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4227
Author(s):  
Alessandro Cossard ◽  
Silvia Casassa ◽  
Carlo Gatti ◽  
Jacques K. Desmarais ◽  
Alessandro Erba
Keyword(s):  
Electron Density ◽  
Chemical Bonding ◽  
Topological Analysis ◽  
Theoretical Description ◽  
Basis Functions ◽  
Quantum Mechanical ◽  
X Ray Diffraction ◽  
X Ray ◽  
Atomic Orbitals ◽  
Uranyl Chloride

The chemistry of f-electrons in lanthanide and actinide materials is yet to be fully rationalized. Quantum-mechanical simulations can provide useful complementary insight to that obtained from experiments. The quantum theory of atoms in molecules and crystals (QTAIMAC), through thorough topological analysis of the electron density (often complemented by that of its Laplacian) constitutes a general and robust theoretical framework to analyze chemical bonding features from a computed wave function. Here, we present the extension of the Topond module (previously limited to work in terms of s-, p- and d-type basis functions only) of the Crystal program to f- and g-type basis functions within the linear combination of atomic orbitals (LCAO) approach. This allows for an effective QTAIMAC analysis of chemical bonding of lanthanide and actinide materials. The new implemented algorithms are applied to the analysis of the spatial distribution of the electron density and its Laplacian of the cesium uranyl chloride, Cs2UO2Cl4, crystal. Discrepancies between the present theoretical description of chemical bonding and that obtained from a previously reconstructed electron density by experimental X-ray diffraction are illustrated and discussed.

Fast analytical evaluation of intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density. III. Application to crystal structures via the Ewald and direct summation methods

2020 ◽  
Vol 76 (6) ◽  
pp. 630-651
Author(s):  
Daniel Nguyen ◽  
Piero Macchi ◽  
Anatoliy Volkov
Keyword(s):  
Interaction Energy ◽  
Crystal Structures ◽  
Electron Density ◽  
Small Molecule ◽  
Electrostatic Interaction ◽  
Multipole Moment ◽  
Interaction Energies ◽  
Acta Cryst ◽  
Löwdin Α Function ◽  
Direct Summation

The previously reported exact potential and multipole moment (EP/MM) method for fast and accurate evaluation of the intermolecular electrostatic interaction energies using the pseudoatom representation of the electron density [Volkov, Koritsanszky & Coppens (2004). Chem. Phys. Lett. 391, 170–175; Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536; Nguyen & Volkov (2019). Acta Cryst. A75, 448–464] is extended to the calculation of electrostatic interaction energies in molecular crystals using two newly developed implementations: (i) the Ewald summation (ES), which includes interactions up to the hexadecapolar level and the EP correction to account for short-range electron-density penetration effects, and (ii) the enhanced EP/MM-based direct summation (DS), which at sufficiently large intermolecular separations replaces the atomic multipole moment approximation to the electrostatic energy with that based on the molecular multipole moments. As in the previous study [Nguyen, Kisiel & Volkov (2018). Acta Cryst. A74, 524–536], the EP electron repulsion integral is evaluated analytically using the Löwdin α-function approach. The resulting techniques, incorporated in the XDPROP module of the software package XD2016, have been tested on several small-molecule crystal systems (benzene, L-dopa, paracetamol, amino acids etc.) and the crystal structure of a 181-atom decapeptide molecule (Z = 4) using electron densities constructed via the University at Buffalo Aspherical Pseudoatom Databank [Volkov, Li, Koritsanszky & Coppens (2004). J. Phys. Chem. A, 108, 4283–4300]. Using a 2015 2.8 GHz Intel Xeon E3-1505M v5 computer processor, a 64-bit implementation of the Löwdin α-function and one of the higher optimization levels in the GNU Fortran compiler, the ES method evaluates the electrostatic interaction energy with a numerical precision of at least 10−5 kJ mol−1 in under 6 s for any of the tested small-molecule crystal structures, and in 48.5 s for the decapeptide structure. The DS approach is competitive in terms of precision and speed with the ES technique only for crystal structures of small molecules that do not carry a large molecular dipole moment. The electron-density penetration effects, correctly accounted for by the two described methods, contribute 28–64% to the total electrostatic interaction energy in the examined systems, and thus cannot be neglected.

Topological analysis of electron density and the electrostatic properties of isoniazid: an experimental and theoretical study

2014 ◽  
Vol 70 (2) ◽  
pp. 331-341 ◽  
Author(s):  
Gnanasekaran Rajalakshmi ◽  
Venkatesha R. Hathwar ◽  
Poomani Kumaradhas
Keyword(s):  
Hydrogen Bonding ◽  
Charge Density ◽  
Electron Density ◽  
Topological Analysis ◽  
Bond Critical Point ◽  
Potential Region ◽  
Electrostatic Properties ◽  
Structural And Electronic Properties ◽  
Density Analysis ◽  
Mycobacterial Cell Wall

Isoniazid (isonicotinohydrazide) is an important first-line antitubercular drug that targets the InhA enzyme which synthesizes the critical component of the mycobacterial cell wall. An experimental charge-density analysis of isoniazid has been performed to understand its structural and electronic properties in the solid state. A high-resolution single-crystal X-ray intensity data has been collected at 90 K. An aspherical multipole refinement was carried out to explore the topological and electrostatic properties of the isoniazid molecule. The experimental results were compared with the theoretical charge-density calculations performed usingCRYSTAL09with the B3LYP/6-31G** method. A topological analysis of the electron density reveals that the Laplacian of electron density of the N—N bond is significantly less negative, which indicates that the charges at the b.c.p. (bond-critical point) of the bond are least accumulated, and so the bond is considered to be weak. As expected, a strong negative electrostatic potential region is present in the vicinity of the O1, N1 and N3 atoms, which are the reactive locations of the molecule. The C—H...N, C—H...O and N—H...N types of intermolecular hydrogen-bonding interactions stabilize the crystal structure. The topological analysis of the electron density on hydrogen bonding shows the strength of intermolecular interactions.

Topological characterization of electron density, electrostatic potential and intermolecular interactions of 2-nitroimidazole: an experimental and theoretical study

2016 ◽  
Vol 72 (5) ◽  
pp. 775-786 ◽  
Author(s):  
Chinnasamy Kalaiarasi ◽  
Mysore S Pavan ◽  
Poomani Kumaradhas
Keyword(s):  
Electron Density ◽  
Intermolecular Interactions ◽  
Electrostatic Potential ◽  
Theoretical Calculations ◽  
Topological Analysis ◽  
X Ray Diffraction ◽  
Topological Characterization ◽  
Data Set ◽  
X Ray ◽  
Charge Concentration

An experimental charge density distribution of 2-nitroimidazole was determined from high-resolution X-ray diffraction and the Hansen–Coppens multipole model. The 2-nitroimidazole compound was crystallized and a high-angle X-ray diffraction intensity data set has been collected at low temperature (110 K). The structure was solved and further, an aspherical multipole model refinement was performed up to octapole level; the results were used to determine the structure, bond topological and electrostatic properties of the molecule. In the crystal, the molecule exhibits a planar structure and forms weak and strong intermolecular hydrogen-bonding interactions with the neighbouring molecules. The Hirshfeld surface of the molecule was plotted, which explores different types of intermolecular interactions and their strength. The topological analysis of electron density at the bond critical points (b.c.p.) of the molecule was performed, from that the electron density ρbcp(r) and the Laplacian of electron density ∇2ρbcp(r) at the b.c.p.s of the molecule have been determined; these parameters show the charge concentration/depletion of the nitroimidazole bonds in the crystal. The electrostatic parameters like atomic charges and the dipole moment of the molecule were calculated. The electrostatic potential surface of the molecule has been plotted, and it displays a large electronegative region around the nitro group. All the experimental results were compared with the corresponding theoretical calculations performed usingCRYSTAL09.

scholarly journals Determination of the electron density in methyl (±)-(1S,2S,3R)-2-methyl-1,3-diphenylcyclopropanecarboxylate using refinements with X-ray scattering factors from wavefunction calculations of the whole molecule

2013 ◽  
Vol 69 (8) ◽  
pp. 910-914 ◽  
Author(s):  
John Bacsa ◽  
John Briones
Keyword(s):  
Electron Density ◽  
Title Compound ◽  
Cyclopropane Ring ◽  
Topological Analysis ◽  
Quantum Mechanical ◽  
Quantum Mechanical Calculations ◽  
X Ray ◽  
Compound C ◽  
X Ray Scattering

The molecule of the title compound, C18H18O2, is a substituted cyclopropane ring. The electron density in this molecule has been determined by refining single-crystal X-ray data using scattering factors derived from quantum mechanical calculations. Topological analysis of the electron densities in the three cyclopropane C—C bonds was carried out. The results show the effects of this substitution on these C—C bonds.

Preliminary Results of a 20 K X-Ray Study of Citrinin

1993 ◽  
Vol 48 (1-2) ◽  
pp. 99-104 ◽  
Author(s):  
R. Destro ◽  
F. Merati
Keyword(s):  
Dipole Moment ◽  
Hydrogen Bonds ◽  
Charge Density ◽  
Topological Analysis ◽  
Coupling Constants ◽  
Molecular Dipole ◽  
X Ray ◽  
A Value ◽  
Quadrupole Coupling ◽  
Asymmetry Parameters

Abstract A total of about 37 000 diffracted intensities has been measured at 20 K for a spherical single crystal of citrinin. Using a multipole formalism to interpret the X-ray data, maps of the charge density and of its Laplacian, as well as for the electrostatic potential have been derived. A value of 7(2) D has been obtained for the magnitude of the molecular dipole moment. A study of the electric field gradient (EFG) at the nuclei has yielded the atomic quadrupole coupling constants (QCC) and asymmetry parameters (η). A topological analysis of the charge density has been performed to characterize the intramolecular covalent and hydrogen bonds.

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