Molecular Electrostatic Potential Values Research Articles

Dihydrogen Binding Affinity of Polyatomic Anions: A DFT Study

The dihydrogen-binding ability of polyatomic oxohalo anions ClO–, ClO2–, ClO3–, ClO4–, BrO–, BrO2–, BrO3–, and BrO4– has been studied at the M06L/6-311++G(d,p) density functional theory and the CCSD(T)/aug-cc-pVTZ//CCSD/aug-cc-pVDZ ab initio theory. The maximum number of dihydrogen adsorbed by the anions (nmax) varies from 17 to 24 in the first coordination shell. As the number of H2 adsorbed varies from 1 to nmax, the oxochloro and oxobromo anions show a wide range for interaction energy (Eint), namely, 1.5–45.4 kcal/mol for the former and 1.4–46.0 kcal/mol for the latter. These results indicate that both series of anions show very similar and high affinity to bind with several dihydrogen molecules. Further, an increase in the coordination ability and a decrease in the strength of the dihydrogen interaction are observed with an increase in the number of oxygen atoms in the polyatomic anion. In contrast, the neutral oxohaloacids show negligible interaction with dihydrogen. The anion···H2 noncovalent interactions along with H···H dihydrogen interactions within the complex are ascertained by locating the bond critical points (bcps) in the quantum theory of atoms in molecules analysis. The electron density at the bcp summed up for all of the anion···H2 interactions (∑ρbcp) showed a strong linear relationship with Eint, indicating that the stability of the complex is due to the formation of a large network of noncovalent bonds in the complex. The amount of electron density donated by the anion to the dihydrogen during complex formation is also gauged from the molecular electrostatic potential values at the nuclei (Vn) of all of the atoms in the anion. The hydrogen uptake leads to a significant reduction in the negative character of Vn, and the total change in Vn from all of the anion atoms (∑ΔVn) is found to be directly proportional to Eint. The polyatomic anions have a very high affinity toward dihydrogen binding, which can be utilized for the development of new hydrogen storage systems.

Structural effects in octahedral carbonyl complexes: an atoms-in-molecules study

In this paper, we assess the ability of descriptors defined within the framework of the quantum theory of atoms-in-molecules to retrieve trans and cis structural effects in 42 d 6 octahedral carbonyl organometallic complexes involving cobalt and rhodium atoms. More specifically, correlations between bond lengths in trans or cis position with respect to common orienting ligands and both local (such as molecular electrostatic potential values or the properties of critical points of the electron density Laplacian field) and integrated (over the metal atomic basin, such as multipolar moments, various energy contributions, condensed conceptual DFT quantities) properties are investigated, casting some light on the physicochemical features that drive this fundamental structural effect.

Conformation analysis of a novel fluorinated chalcone.

Chalcones are an important class of natural compounds that exhibit numerous biological activities. In this paper, we report the synthesis and characterization of new fluorinated chalcone (FCH). The molecular geometry was determined by means of single crystal X-ray diffraction, and density functional theory (DFT) at B3LYP, M06-2X functionals and MP2 method, with the 6-311++G(d,p) basis set, was applied to optimize the ground state geometry and to study the molecular conformational stability. The molecular electrostatic potential (MEP) was also investigated at the same level of theory in order to identify and quantify the possible reactive sites. The FCH crystallizes in the centrossymmetric space group [Formula: see text] with two independent conformers (α and β) in the asymmetric unit cell. The α conformer is arranged in planar layer whereas the β creates a layer of non-classical dimer along c axis, that differ from α in about 11° in the orientation of phenyl groups. The stabilization of the β conformer is achieved by C-H···π arrangement. The small energy difference between the conformers (0.086 kcal mol-1) and the absence of activation energy indicates that the conversion between them can takes place at room temperature and the β isomer is stable only in solid state. The FCH most electrophilic site occurs on the oxygen atom from the carboxyl group with absolute MEP value of about -52 kcal mol-1 whereas the MEP value calculated for F site is about -23 kcal mol-1.

A systematic structural study of halogen bonding versus hydrogen bonding within competitive supramolecular systems.

As halogen bonds gain prevalence in supramolecular synthesis and materials chemistry, it has become necessary to examine more closely how such interactions compete with or complement hydrogen bonds whenever both are present within the same system. As hydrogen and halogen bonds have several fundamental features in common, it is often difficult to predict which will be the primary interaction in a supramolecular system, especially as they have comparable strength and geometric requirements. To address this challenge, a series of molecules containing both hydrogen- and halogen-bond donors were co-crystallized with various monotopic, ditopic symmetric and ditopic asymmetric acceptor molecules. The outcome of each reaction was examined using IR spectroscopy and, whenever possible, single-crystal X-ray diffraction. 24 crystal structures were obtained and subsequently analyzed, and the synthon preferences of the competing hydrogen- and halogen-bond donors were rationalized against a background of calculated molecular electrostatic potential values. It has been shown that readily accessible electrostatic potentials can offer useful practical guidelines for predicting the most likely primary synthons in these co-crystals as long as the potential differences are weighted appropriately.

Generative topographic mapping of binding pocket of β2 receptor and three‐way partial least squares modeling of inhibitory activities

The visualization and characterization of protein pockets is the starting point for many structure‐based drug design projects. The size and shape of protein pockets dictate 3D geometry of ligands that can strongly inhibit the following biological events. Thus, a minimal requirement for inhibition is that a molecule sterically binds the active site with some allowance for induced fit. Methods for direct display of active sites in a protein have become prevalent in recent years.In this study, a new mapping method, generative topographic mapping, is investigated to describe the 3D surface of protein pocket. The β2 receptor protein is used as a benchmark. By mapping the molecular surface points and assigning the associated molecular electrostatic potential (MEP) values, the original 3D structure of the active site is well reproduced by the 2D latent map in generative topographic mapping. The distributions of MEP values of two 2D latent maps derived from the inhibitor and the β2 receptor protein are well complemented. Using three‐way partial least squares modeling, a predictive model linking the inhibitory activity and their MEP values can be constructed, which was not feasible in the previous spherical self‐organizing map studies. The resulting regression coefficient matrix of the three‐way partial least squares model has many insights for understanding the structural requirements for β2 inhibitory activity. Copyright © 2014 John Wiley & Sons, Ltd.

Does the Molecular Electrostatic Potential Reflect the Effects of Substituents in Aromatic Systems?

A detailed analysis of the molecular electrostatic potential (MEP) at selected positions in molecular space was performed for a series of substituted benzene derivatives. We show that appropriately selected MEP values can quantitatively reflect the regiospecific effects of substituents on the aromatic ring. Theoretically evaluated electrostatic potentials in close proximity to the ring carbon atoms reflect well both through-space and resonance effects and excellent correlation is established between the MEP values and substituent constants. The best descriptor of the local properties at different ring positions is the electrostatic potential at nuclei (EPN).

Molecular electrostatics for probing lone pair–π interactions

An electrostatics-based approach has been proposed for probing the weak interactions between lone pair containing molecules and π deficient molecular systems. For electron-rich molecules, the negative minima in molecular electrostatic potential (MESP) topography give the location of electron localization and the MESP value at the minimum (Vmin) quantifies the electron-rich character of that region. Interactive behavior of a lone pair bearing molecule with electron deficient π-systems, such as hexafluorobenzene, 1,3,5-trinitrobenzene, 2,4,6-trifluoro-1,3,5-triazine and 1,2,4,5-tetracyanobenzene explored within DFT brings out good correlation of the lone pair-π interaction energy (E(int)) with the Vmin value of the electron-rich system. Such interaction is found to be portrayed well with the Electrostatic Potential for Intermolecular Complexation (EPIC) model. On the basis of the precise location of MESP minimum, a prediction for the orientation of a lone pair bearing molecule with an electron deficient π-system is possible in the majority of the cases studied.

Stabilization of Si(0) and Ge(0) compounds by different silylenes and germylenes: a density functional and molecular electrostatic study

Recently, the chemistry of element (0) compounds has attracted the attention of both experimental and theoretical chemists. In this article, some new Si(0) and Ge(0) compounds stabilized by different silylene and germylene ligands are studied theoretically by applying quantum chemical calculations and topography mapping of molecular electrostatic potential (MESP). These compounds are found to have high donor-acceptor bond strengths and are thermodynamically stable. The nature of the molecular orbitals, negative values of MESP at its critical points, as well as proton affinity values suggest that they are very good nucleophiles. Calculated proton affinity values suggest the possible isolation of their diprotonated salts.

New description of protein–ligand interactions using a spherical self-organizing map

In a previous report, we studied the mapping ability of the spherical self-organizing map (SSOM). The original 3D structure of the active site of the β2 protein structure was well reproduced by the SSOM. To validate the geometrical transformation and the resulting molecular electrostatic potential (MEP) distribution, the molecular surfaces of 20 β2 ligands were mapped onto the protein SSOM sphere. The MEP values of the two spheres derived from the ligand and the β2 receptor protein were compared. In most cases involving potent ligands, the two spheres had a moderate negative correlation. This indicates that the SSOM approach has excellent potential to represent a complex protein surface as a simple spherical structure.In this study, we perform a quantitative structure–activity relationship (QSAR) study of caspase-3 inhibitors based on the SSOM technique. Initially, the active site of the protein structure ‘caspase-3’ was characterized by the SSOM using the MEP values. Each inhibitor was then projected onto the protein SSOM sphere and the chemical descriptors were derived from the ligand SSOM sphere. The correlation of the chemical descriptors and the inhibitory activities was investigated using the support vector regression (SVR) method. Finally, the important MEP descriptors from the final SVR model were examined. The structural requirements of caspase-3 inhibitors are discussed from the perspectives of both the ligand and protein structures.

A New Method for Mapping the Molecular Surface of a Protein Structure Using a Spherical Self-Organizing Map.

A spherical self-organizing map (SSOM) was applied for mapping the molecular surface of a protein structure on a spherical structure. The active site of the X-ray crystal structure of β2 receptor protein was used for this purpose. After mapping the molecular surface points and assigning the associated molecular electrostatic potential (MEP) values, the original 3D structure of the active site was well reproduced by the SSOM. In order to validate the geometrical transformation and the resulting MEP distribution, the molecular surfaces of twenty β2 ligands were mapped on the established SSOM sphere. The MEP values of two spheres derived from the ligand and the β2 receptor protein were compared. In almost all cases of strong ligands, the two spheres had a moderate negative correlation.

Interaction between anions and substituted molecular bowls

Complexes formed by anions and substituted molecular bowls were studied by means of computational methods. The bowls consisted of corannulene molecules substituted with five or ten F, Cl, or CN groups, whereas Cl(-), Br(-) and BF(4)(-) were the anions considered. Substitution with F, Cl and CN hardly affects the geometry of the bowl, but produces an inversion of the molecular electrostatic potential of the bowls, which becomes positive over the two faces of the bowl, therefore interacting favorably with anions. In all cases considered, the most stable complex presents the anion interacting with the concave side of the bowl. The strength of the interaction roughly follows the values of molecular electrostatic potential, being more stable as more positive is the potential. The preference of anions to interact with the concave side of the bowls has its origin in stronger electrostatic and dispersion interactions. Though the solvent produces an important decrease in the stability of the complexes, the results suggest the possibility of employing these substituted buckybowls as anion receptors with a preferential concave complexation, especially for large anions.

Assessment of Stereoelectronic Effects in Grubbs First-Generation Olefin Metathesis Catalysis Using Molecular Electrostatic Potential

Quantum mechanically derived molecular electrostatic potential (MESP) based descriptors have been proposed for the assessment of both the steric and electronic effects of phosphines in several first-generation Grubbs olefin metathesis catalysts. The MESP at the P nucleus of the active form of the catalyst Cl2(PR3)Ru═CH2 (1) and its ethylene-coordinated complex (2) are determined. Further, frozen structures corresponding to 1 and 2 are located by replacing the P−R bonds with P−H bonds. The MESP at the P of a frozen geometry is free from the electronic effect of R but is influenced by steric effects due to the structural restrictions imposed in the geometry. The difference between the MESP values at the P nucleus of Cl2(PH3)Ru═CH2 and Cl2(PR3)Ru═CH2 is taken as a measure of the combined steric and electronic effects of PR3 (VSE1) in 1. Similarly, the combined steric and electronic effect of PR3 in 2 (VSE2) is also calculated. The frozen structures allowed calculation of the steric-only effects for 1 (VS1) a...

Additivity of substituent effects on the proton affinity and gas-phase basicity of pyridines

The change in the proton affinity (PA) and basicity (GB) of pyridine with substituents have been considered by quantum mechanical methods at the B3LYP/6-311++G(d,p) level of theory. The PA and GB values increase by the electron-donating substituents and decrease by the electron-withdrawing substituents. The effects of substituents on the PA and GB are approximately additive. The deviations of changes that are predicted from the additivity of substituent effects are generally lower than 30% from the calculated changes. Linear relationships are observed between the calculated PA values of substituted pyridines and the topological properties of electron density, the molecular electrostatic potentials (MEP), and the N–H bond lengths. In addition, well-defined relations are established between the calculated PA values and the Hammett constants, and the reaction constant ( ρ) has been calculated for the protonation reaction. With some exceptions, the effect of substituents are also additive on the electron density and its Laplacian calculated at N–H BCP, and the MEP values calculated around the N atom.

Molecular electrostatic potential for exploring π-conjugation: a density-functional investigation

Molecular electrostatic potentials (MESP) of the most common building blocks of organic π-conjugated systems, viz. ethylene, acetylene, benzene, furan, pyrrole, thiophene and phenylvinylene, are examined at the B3LYP/6-311++G(2d,2p) level. The topography of MESP is employed for mapping the strength of electronic conjugation between these building blocks. When electron-rich molecular regions are connected to each other, the MESP value of the corresponding conjugation critical point (CCP) is able to provide a quantitative measure of the strength of the conjugation. The systems with stronger conjugation are generally seen to possess a larger negative value of CCP and a smaller difference (ΔV(CM-CCP)) between the MESP values of respective conjugated minimum (CM) and the CCP, in agreement with the experimental as well as other theoretical results. The present MESP topography-based approach thus offers a measure of the quantitative strength of π-conjugation in molecules.

Radial scan of the molecular electrostatic potential of RNA double helices: An application to the enzyme-tRNA recognition

We introduced a method to characterize quantitatively the molecular electrostatic potential (MEP) of the minor and major grooves of base pairs located at nucleic acid double helices. By means of a radial MEP scan, we obtained a n-tuple of potential values corresponding to each groove, which can be analyzed by plotting the MEP values as a function of the angle in the radial scan. We studied base pairs of two different tRNAs, relevant in the recognition process with their cognate aminoacyl tRNA synthetases (aaRSs), in order to correlate their electrostatic behavior with the corresponding aminoacylation activity. We analyzed the first three base pairs of the Escherichia coli tRNA Ala acceptor stem, finding several cases where the MEP profiles obtained from the plots are in agreement with the reported aminoacylation activities. Additionally, a non-hierarchical clustering performed over the MEP n-tuples resulted in meaningful classifications that correlate with the activity and with the predicted stereochemistry of the reaction. We also studied the first two base pairs of the E. coli tRNA Thr acceptor stem but constraining the analysis to the angle intervals that seem relevant for the binding sites of the enzyme. These intervals were deduced from the ThrRS-tRNA Thr complex crystal structure. In this case, we also found a good agreement between the MEP profiles and the activity, supporting the idea that the tRNA identity elements function is to allow an optimal electrostatic complementarity between the aminoacyl-tRNA synthetase and the tRNA.

New Quantum Mechanics-Based Three-Dimensional Molecular Descriptors for Use in QSSR Approaches: Application to Asymmetric Catalysis

This paper presents a new protocol based on 3D molecular descriptors using QM calculations for use in CoMFA-like 3D-QSSR. The new method was developed and then applied to predict catalytic selectivity in the asymmetric alkylation of aldehydes catalyzed by Zn-aminoalcohols. The molecular descriptors are obtained straightforwardly from the electronic charge density function, rho(r), and the molecular electrostatic potential (MEP) distributions. The chemically meaningful Molecular Shape Field (MSF) descriptor that accounts for the shape properties of the catalyst is defined from rho(r). Alignment independence was achieved by computing the product of the MSF and MEP values of pairs of points over a given distance range on a molecular isosurface and then selecting the product with the highest value. The new QSSR method demonstrated good predictive ability (q2 = 0.79) when full cross-validation procedures were carried out. Accurate predictions were made for a larger data set, although some deviations occurred in the predictions for catalytic systems with low enantiodiscrimination. Analysis of this QSSR model allows for the following: (1) evaluation of the contribution of each functional group to enantioselectivity and (2) the molecular descriptors to be related to previously proposed stereochemical models for the reaction under study.

Features of absorption and fluorescence spectra of prodan

Some important and essential features of absorption and fluorescence spectra of prodan in homogeneous and binary mixes are studied. According to results obtained from experimental and quantum-chemical researches we show that the absorption spectrum of prodan in nonpolar solvent within 25,000–50,000 cm −1 is formed by eight electronic transitions. Quantum-chemical calculations are performed in the geometry of both the ground and exited states of prodan. The rate constants of photoprocesses and the quantum yield of fluorescence are determined for the prodan and its complexes with water. A dramatic shift of the fluorescence band at changing from nonpolar solvent to isopropyl alcohol and water is explained. The roles of general solvent effects and specific interactions are separated. According to values of molecular electrostatic potential and charges on atoms the centers of possible interaction of prodan with a solvent are obtained. Possible models of prodan complexes in water are offered. The results of quantum-chemical calculation for offered complexes of prodan in water are compared with those for the free prodan molecule. The presence of the second band (about 24,000 cm −1) in fluorescence spectra of prodan in isopropyl (ethyl) alcohol–water solvents is explained.

A theoretical study of some new analogues of the anti-cancer drug camptothecin

The enzyme topoisomerase I (topo I), which is essential for cell replication, transiently causes a DNA single strand break and makes a complex with it. The anti-cancer agent camptothecin (CPT) binds to the topo I-DNA complex and stabilizes it, preventing resealing of the broken DNA strand and cell growth. Considering the structural factors of CPT that are believed to be involved in stabilizing the topo I-DNA complex via hydrogen bonding and stacking interactions, designs of two new analogues of CPT (topo I inhibitors) have been suggested. The molecular geometries of CPT, two of its analogues and certain other related molecules included in the study were fully optimized in both gas phase and aqueous media at the B3LYP/6-311++G(d,p) level of density functional theory. Solvation effects of aqueous media were treated using the polarizable continuum model (PCM). Net CHelpG charges and surface molecular electrostatic potentials (MEP) near the atomic sites of the molecules were studied. Structural analogy and surface MEP values suggests that the two new CPT analogues studied here would be potent topoisomerase I inhibitors.

Structure, reactivity and aromaticity of acenes and their BN analogues: a density functional and electrostatic investigation.

Density functional calculations have been carried out on a series of linearly annelated acenes and their BN analogues. Even though borazine shows aromatic and reactivity behavior parallel with that of benzene, its condensed derivatives show patterns different from those of their hydrocarbon analogues. Nucleus independent chemical shift (NICS) values in acenes suggest that the aromaticity of the inner rings is more than that of benzene, whereas in BN-acenes there is no substantial change in the aromaticity of the individual rings. Molecular electrostatic potential (MESP) is employed to obtain further insights into the bonding and reactivity trends for these systems. The MESP topography patterns of acenes and BN-acenes are substantially different, with BN-acenes showing more localized pi electron features compared to those of acenes. The MESP values at the critical points (CPs) indicate overall lowering of aromaticity in these annelated systems. However, this change is gradual among the BN-acenes.

3D-QSAR study of antifungal N-myristoyltransferase inhibitors by comparative molecular surface analysis

The correlation between the molecular electrostatic potential (MEP) on benzofuran inhibitors and the N-myristoyltransferase (Nmt) inhibitory activity is investigated by a three-dimensional quantitative structure–activity relationship (3D-QSAR) approach. To each compound, a Kohonen neural network (KNN) is used to project the MEP values on a Connolly surface into a two-dimensional map. Each node in the KNN map is coded by the associated MEP value of the occupying sampling point and all the coding nodes are collected together to define chemical descriptors. The best partial least squares (PLS) model with the selected descriptors is searched among the possible candidate models by genetic algorithm (GA). The resulting best model is significantly more predictive than the one with all chemical descriptors. The model has given additional information about the binding of a benzofuran inhibitor to Nmt.