REG-MULTI: Lifting the veil on electrostatic interactions

Falcioni, Fabio; Symons, Benjamin C.B.; Popelier, Paul L.A.

doi:10.1016/bs.aiq.2023.03.001

Cited by 4 publications

(5 citation statements)

References 50 publications

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“…REG analysis was carried out with the updated inhouse code package 44 REG.py, which supersedes the program ANANKE. Visualization and model handling were executed with the program 48 GaussView6, the open source package 49 PyMol, and a custom 50 PyMol-REG plugin.…”

Section: Methodsmentioning

confidence: 99%

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How to Compute Atomistic Insight in DFT Clusters: The REG-IQA Approach

Falcioni

Popelier

2023

J. Chem. Inf. Model.

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The relative energy gradient (REG) method is paired with the topological energy partitioning method interacting quantum atoms (IQA), as REG-IQA, to provide detailed and unbiased knowledge on the intra-and interatomic interactions. REG operates on a sequence of geometries representing a dynamical change of a system. Its recent application to peptide hydrolysis of the human immunodeficiency virus-1 (HIV-1) protease (PDB code: 4HVP) has demonstrated its full potential in recovering reaction mechanisms and through-space electrostatic and exchange−correlation effects, making it a compelling tool for analyzing enzymatic reactions. In this study, the computational efficiency of the REG-IQA method for the 133-atom HIV-1 protease quantum mechanical system is analyzed in every detail and substantially improved by means of three different approaches. The first approach of smaller integration grids for IQA integrations reduces the computational overhead by about a factor of 3. The second approach uses the line-simplification Ramer− Douglas−Peucker (RDP) algorithm, which outputs the minimal number of geometries necessary for the REG-IQA analysis for a predetermined root mean squared error (RMSE) tolerance. This cuts the computational time of the whole REG analysis by a factor of 2 if an RMSE of 0.5 kJ/mol is considered. The third approach consists of a "biased" or "unbiased" selection of a specific subset of atoms of the whole initial quantum mechanical model wave-function, which results in more than a 10-fold speed-up per geometry for the IQA calculation, without deterioration of the outcome of the REG-IQA analysis. Finally, to show the capability of these approaches, the findings gathered from the HIV-1 protease system are also applied to a different system named haloalcohol dehalogenase (HheC). In summary, this study takes the REG-IQA method to a computationally feasible and highly accurate level, making it viable for the analysis of a multitude of enzymatic systems.

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Section: Methodsmentioning

confidence: 99%

“…REG-IQA results for both V xc and V cl are presented in Figure 12 using the PyMol-REG 50 plugin. The full system and two truncations (37 and 88 atoms, respectively) are analyzed to show the potential of the systematic truncation.…”

Section: Reg-iqa Of the Hhec Systemmentioning

confidence: 99%

How to Compute Atomistic Insight in DFT Clusters: The REG-IQA Approach

Falcioni

Popelier

2023

J. Chem. Inf. Model.

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“…Note that the ωB97X-D functional is not available in AIMAll. The REG analysis was carried out via the REG.py program developed by Popelier's group [53].…”

Section: Methodsmentioning

confidence: 99%

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds

Domingo,

Aurell,

Ríos-Gutiérrez

2023

Molecules

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The reaction of N-phenyl iminoborane with benzaldehyde yielding a fused aromatic compound, recently reported by Liu et al., has been studied within the Molecular Electron Density Theory (MEDT). Formation of the fused aromatic compound is a domino process that comprises three consecutive reactions: (i) formation of a weak molecular complex between the reagents; (ii) an intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent of iminoborane; and (iii) a formal 1,3-hydrogen shift yielding the final fused aromatic compound. The two last steps correspond to a Friedel–Crafts acylation reaction, the product of the second reaction being the tetrahedral intermediate of an electrophilic aromatic substitution reaction. However, the presence of the imino group adjacent to the aromatic ring strongly stabilizes the corresponding intermediate, being the reaction product when the ortho positions are occupied by t-butyl substituents. This domino reaction shows a great similitude with the Brønsted acid catalyzed Povarov reaction. Although N-phenyl iminoborane can experience a formal [2+2] cycloaddition reaction with benzaldehyde, its higher activation Gibbs free energy compared to the intramolecular electrophilic attack of the activated carbonyl carbon of benzaldehyde on the ortho position of the N-phenyl substituent, 6.6 kcal·mol−1, prevents the formation of the formal [2+2] cycloadduct. The present MEDT study provides a different vision of the molecular mechanism of these reactions based on the electron density.

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“…Moreover, the multipolar expansion of the interatomic electrostatic energy reveals this energy’s fine structure. We call this method REG-MULTI . The energies are also analyzed using REG-IQF (F = fragments), which is a straightforward extension of REG-IQA thanks to the additivity of topological atoms.…”

Section: Introductionmentioning

confidence: 99%

“…We call this method REG-MULTI. 23 The energies are also analyzed using REG-IQF (F = fragments), which is a straightforward extension of REG-IQA thanks to the additivity of topological atoms. Note that when empirical dispersion corrections (such as the D3 dispersion correction) are employed in connection with density functional theory (DFT) calculations, these can be readily paired with the IQA energy partitioning.…”

Section: Introductionmentioning

confidence: 99%

Interacting Quantum Atoms and Multipolar Electrostatic Study of XH···π Interactions

Triestram,

Falcioni,

Popelier

2023

ACS Omega

Self Cite

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The interaction energies of nine XH···π (X = C, N, and O) benzene-containing van der Waals complexes were analyzed, at the atomic and fragment levels, using QTAIM multipolar electrostatics and the energy partitioning method interacting quantum atoms/fragment (IQA/IQF). These descriptors were paired with the relative energy gradient method, which solidifies the connection between quantum mechanical properties and chemical interpretation. This combination provides a precise understanding, both qualitative and quantitative, of the nature of these interactions, which are ubiquitous in biochemical systems. The formation of the OH···π and NH···π systems is electrostatically driven, with the Q zz component of the quadrupole moment of the benzene carbons interacting with the charges of X and H in XH. There is the unexpectedly intramonomeric role of X–H (X = O, N) where its electrostatic energy helps the formation of the complex and its covalent energy thwarts it. However, the CH···π interaction is governed by exchange–correlation energies, thereby establishing a covalent character, as opposed to the literature’s designation as a noncovalent interaction. Moreover, dispersion energy is relevant, statically and in absolute terms, but less relevant compared to other energy components in terms of the formation of the complex. Multipolar electrostatics are similar across all systems.

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REG-MULTI: Lifting the veil on electrostatic interactions

Cited by 4 publications

References 50 publications

How to Compute Atomistic Insight in DFT Clusters: The REG-IQA Approach

How to Compute Atomistic Insight in DFT Clusters: The REG-IQA Approach

A Molecular Electron Density Theory Study of the Domino Reaction of N-Phenyl Iminoboranes with Benzaldehyde Yielding Fused Bicyclic Compounds

Interacting Quantum Atoms and Multipolar Electrostatic Study of XH···π Interactions

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