An Electron Density‐Based Approach to the Origin of Stacking Interactions

Mosquera, Ricardo A.; Moa, María J. González; Estévez, Laura; Mandado, Marcos; Graña, Ana M.

doi:10.1002/9783527629213.ch11

Cited by 12 publications

(5 citation statements)

References 79 publications

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“…The topological analysis of the electron density constitutes a powerful tool to investigate the electronic properties of the molecular system and allows a deep examination of the molecular interactions. This methodology has been successfully applied in the study of the properties of a variety of conventional and unconventional hydrogen bonds (HBs), aromatic HBs as well as π···π stacking interactions. − From QTAIM calculations, it is possible to determine in an unequivocal way the different strong and weak interactions between two atoms observing the existence of bond critical points (BCPs) and their respective bond paths. It should be noted that this detailed analysis is not possible only from the evaluation of the geometrical parameters (bond distances and angles).…”

Section: Resultsmentioning

confidence: 99%

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Tosso¹,

Andújar²,

Gutiérrez³

et al. 2013

J. Chem. Inf. Model.

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A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC₅₀ values was obtained, predicting with an acceptable qualitative accuracy the potential inhibitor effect of nonsynthesized compounds. Such correlation was experimentally corroborated synthesizing and testing two new inhibitors reported in this paper.

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Section: Resultsmentioning

confidence: 99%

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Tosso¹,

Andújar²,

Gutiérrez³

et al. 2013

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

“…The topological analysis of the electron density constitutes a powerful tool for investigating the electronic properties of the molecular system and allows for a deep examination of the molecular interactions. This methodology has been successfully applied in the study of the properties of a variety of conventional and unconventional HBs, aromatic HBs, and π–π stacking. − …”

Section: Resultsmentioning

confidence: 99%

“…Taking advantage of structural information available from different experimental and theoretical studies of DA at the D 2 dopamine receptor (D2–DR) structure, we performed a comprehensive conformational study of DA interacting with this D2 receptor, using a combination of molecular dynamics (MD) simulations and semiempirical and DFT calculations. In addition, a detailed electronic analysis using quantum theory of atoms in molecules (QTAIM) − techniques was carried out for the different complexes obtained.…”

Section: Introductionmentioning

confidence: 99%

Searching the “Biologically Relevant”Conformation of Dopamine: A Computational Approach

Andújar

Tosso

Suvire

et al. 2011

J. Chem. Inf. Model.

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We report here an exhaustive and complete conformational study on the conformational potential energy hypersurface (PEHS) of dopamine (DA) interacting with the dopamine D2 receptor (D2-DR). A reduced 3D model for the binding pocket of the human D2-DR was constructed on the basis of the theoretical model structure of bacteriorhodopsin. In our reduced model system, only 13 amino acids were included to perform the quantum mechanics calculations. To obtain the different complexes of DA/D2-DR, we combined semiempirical (PM6), DFT (B3LYP/6-31G(d)), and QTAIM calculations. The molecular flexibility of DA interacting with the D2-DR was evaluated from potential energy surfaces and potential energy curves. A comparative study between the molecular flexibility of DA in the gas phase and at D2-DR was carried out. In addition, several molecular dynamics simulations were carried out to evaluate the molecular flexibility of the different complexes obtained. Our results allow us to postulate the complexes of type A as the "biologically relevant conformations" of DA. In addition, the theoretical calculations reported here suggested that a mechanistic stepwise process takes place for DA in which the protonated nitrogen group (in any conformation) acts as the anchoring portion, and this process is followed by a rapid rearrangement of the conformation allowing the interaction of the catecholic OH groups.

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“…15 Energy Fragmentation vs Deformation Density Plots. Together with other local properties of the electron density, 16 deformation density plots can be employed to rationalize at the qualitative level the stability of hydrogen bonding, 17 stacking, 18 or anion-π complexes. 19 These deformation density plots are also frequently employed to evaluate the strength of chemical bonds.…”

Section: Examplesmentioning

confidence: 99%

“…Together with other local properties of the electron density, deformation density plots can be employed to rationalize at the qualitative level the stability of hydrogen bonding, stacking, or anion-π complexes . These deformation density plots are also frequently employed to evaluate the strength of chemical bonds. , In the case of intermolecular interactions, deformation density plots are more properly obtained as the difference between the one-electron density of the complex and the summation of the one-electron densities of the noninteracting monomers.…”

Section: Examplesmentioning

confidence: 99%

Electron Density Based Partitioning Scheme of Interaction Energies

Mandado

Hermida-Ramón

2011

J. Chem. Theory Comput.

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In this paper, a new partitioning of the complex interaction energy is proposed. This new partitioning is based on the decomposition of the one-electron and exchange-correlation densities into unperturbed and deformation densities. Thus, the proposed energy fragmentation can be applied at the SCF level and post-SCF levels as long as the corresponding density matrices have been evaluated previously. It provides the typical description of the complex interaction as a summation of electrostatic, exchange-repulsion, and polarization terms. However, the new method allows splitting up the exchange-repulsion into exchange and Pauli-repulsion energies. A full theoretical description of the method is presented, and some examples of its application to small complexes are discussed. A comparison with results obtained using perturbation methods is also carried out, showing that the first order terms obtained from symmetry adapted perturbation theories are perfectly reproduced with the new method. A clear bridge between qualitative deformation density plots and quantitative measures of the interaction energy components can be established within the framework of this new partitioning scheme, giving rise to a graphical and very intuitive interpretation of the complex formation.

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An Electron Density‐Based Approach to the Origin of Stacking Interactions

Cited by 12 publications

References 79 publications

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Molecular Modeling Study of Dihydrofolate Reductase Inhibitors. Molecular Dynamics Simulations, Quantum Mechanical Calculations, and Experimental Corroboration

Searching the “Biologically Relevant”Conformation of Dopamine: A Computational Approach

Electron Density Based Partitioning Scheme of Interaction Energies

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