Influence of polarization functions on molecular electrostatic potentials

We study the effects of d-polarization functions, centered on the heavy atoms, on the SCF molecular electrostatic potentials calculated for some molecules. The positions and energies of the minima found are very sensitive to the inclusion of polarization functions in the basis set used. The variations depend on the heavy atom involved and on the possible anisotropy of its charge distribution. These variations are particularly important for second-row atoms.     

Computed electrostatic potentials and average local ionization energies on the molecular surfaces of some tetracyclines

The electrostatic potentials and average local ionization energies computed on the molecular surfaces of four tetracyclines have been investigated with the objective of identifying common features as well as subtle differences that may be related to their biological activities. The four are the parent molecule tetracycline, chlortetracycline, oxytetracycline, and doxycyline. The calculations were carried out at the HF/STO‐3G*//STO‐3G* level. Our electrostatic potential results show that each molecule has a large negative region that extends along its lower portion, consistent with its ability to complex Ca²⁺ and Mg²⁺ ions. Although the surface electrostatic potentials of the four tetracyclines show many similarities, our statistical measure of local polarity allows us to label doxycycline as the one with the lowest degree of local polarity, consistent with its longer half‐life in vivo. The regions in the tetracyclines with the most reactive electrons are the amide nitrogen lone pairs and certain carbons of the outermost rings. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 82: 160–169, 2001     

Representation of molecular electrostatic potentials of biopolymer by self‐organizing feature map

The Kohonen self‐organizing map was introduced to map the protein molecular surface features. The protein or polypeptide properties, such as shape and molecular electrostatic potential, can be visualized by self‐organizing map, which was trained by the 3D surface coordinates. Such maps allow the visual comparison of molecular properties between proteins having common topological or chemical features.     

Molecular electrostatic potentials as input for the alignment of HIV-1 integrase inhibitors in 3D QSAR

Comparative molecular similarity indices analysis (CoMSIA), a three-dimensional quantitative structure activity relationship (3D QSAR) paradigm, was used to examine the correlations between the calculated physicochemical properties and the in vitro activities (3'-processing and 3'-strand transfer inhibition) of a series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors. The training set consisted of 34 molecules from five structurally diverse classes: salicylpyrazolinones, dioxepinones, coumarins, quinones, and benzoic hydrazides. The data set was aligned using extrema of molecular electrostatic potentials (MEPs). The predictive ability of the resultant model was evaluated using a test set comprised of 7 molecules belonging to a different structural class of thiazepinediones. A CoMSIA model using an MEP-based alignment showed considerable internal as well external predictive ability (r2(cv) = 0.821, r2(pred) = 0.608 for 3'-processing; and r2(cv) = 0.759, r2(pred.) = 0.660 for 3'-strand transfer).     

Prediction of densities for solid energetic molecules with molecular surface electrostatic potentials

The densities of high energetic molecules in the solid state were calculated with a simplified scheme based on molecular surface electrostatic potentials (MSEP). The MSEP scheme for density estimation, originally developed by Politzer et al., was further modified to calculate electrostatic potential on a simpler van der Waals surface. Forty-one energetic molecules containing at least one nitro group were selected from among a variety of molecular types and density values, and were used to test the suitability of the MSEP scheme for predicting the densities of solid energetic molecules. For comparison purposes, we utilized the group additivity method (GAM) incorporating the parameter sets developed by Stine (Stine-81) and by Ammon (Ammon-98 and -00). The absolute average error in densities from our MSEP scheme was 0.039 g/cc. The results based on our MSEP scheme were slightly better than the GAM results. In addition, the errors in densities generated by the MSEP scheme were almost the same for various molecule types, while those predicted by GAM were somewhat dependent upon the molecule types.     

On the molecular electrostatic potentials obtained with CNDO and INDO wave functions

Molecular electrostatic potentials computed with CNDO/2 and INDO wave functions are shown to present systematic differences with respect to ab initio potentials in the case of out-of-plane potentials and in-plane vicinal hetero atoms in planar hetero molecules.     

Quantum chemical study on the interaction of some bisphosphonates and Ca2+: The role of molecular electrostatic potentials in the prediction of binding geometry

Summary Molecular electrostatic potentials have been used to model the calcium binding properties of some bisphosphonate drugs, which are used to treat various bone diseases. The mechanism of action involves the binding of bisphosphonates to the bone surface, where calcium plays an important role. Electrostatic potential maps derived from ab initio partial charges have been compared with both the crystal structure and the fully optimized ab initio structure of (dichloro)methylenebisphosphonate-calcium ion complex. Molecular electrostatic potentials can correctly predict the calcium binding geometry of bisphosphonate-type compounds and this type of information can be used in the practical drug design work.     

Structures and molecular surface electrostatic potentials of high-density C,N, H systems

Tri-s-triazine and two ditetrazolodiazines are known to have unusually high crystal densities (for unsubstituted C, N, H compounds). We have used a nonlocal density functional procedure to compute the geometries and energies of these and three related molecules, and then calculated the ab initio SCF electrostatic potentials on their molecular surfaces. We attribute the high densities to the relatively small molecular volumes and the strong intermolecular attractions arising from highly varying surface potentials. The energy differences of the two ditetrazoles and their diazide tautomers were computed, as well as for the dinitro derivative of one of the former.     

Predicting reduction potentials of 1,3,6‐triphenyl fulvenes using molecular electrostatic potential analysis of substituent effects

The influence of mono‐ and multiple substituent effect on the reduction potential (E⁰) of 1,3,6‐triphenyl fulvenes is investigated using B3LYP‐SMD/6‐311+G(d,p) level density functional theory. The molecular electrostatic potential (MESP) minimum at the fulvene π‐system (V_min) and the change in MESP at any of the fulvene carbon atoms (ΔV_C) for both neutral and reduced forms are used as excellent measures of substituent effect from the para and meta positions of the 1,3 and 6‐phenyl moieties. Substitution at 6‐phenyl para position has led to significant change in E⁰ than any other positions. By applying the additivity rule of substituent effects, an equation in ΔV_C is derived to predict E⁰ for multiply substituted fulvenes. Further, E⁰ is predicted for a set of 2000 hexa‐substituted fulvene derivatives where the substituents and their positions in the system are chosen in a random way. The calculated E⁰ agreed very well with the experimental E⁰ reported by Godman et al. Predicting E⁰ solely by substituent effect offers a simple and powerful way to select suitable combinations of substituents on fulvene system for light harvesting applications. © 2018 Wiley Periodicals, Inc.     

Molecular surface electrostatic potentials in the analysis of non-hydrogen-bonding noncovalent interactions

Electrostatic potentials computed on molecular surfaces are used to analyse some noncovalent interactions that are not in the category of hydrogen bonding, e.g. “halogen bonding”. The systems examined include halogenated methanes, substituted benzenes,s-tetrazine and l,3-bisphenylurea. The data were obtained byab initio SCF calculations.     

Accurate conformation‐dependent molecular electrostatic potentials for high‐throughput in silico drug discovery

The atom‐centered partial charges‐approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the efficiency of ab initio methods. Here, we report on new parameters for the EEM and SFKEEM electronegativity equalization‐based methods for rapidly determining partial charges that will accurately model the electrostatic potential of flexible molecules. The developed parameters cover most pharmaceutically relevant chemistries, and charges obtained using these parameters reproduce the B3LYP/cc‐pVTZ reference electrostatic potential of a set of FDA‐approved drug molecules at best to an average accuracy of 13 ± 4 kJ mol^?1; thus, equipped with these parameters electronegativity equalization‐based methods rival the current best non‐quantum mechanical methods, such as AM1‐BCC, in accuracy, yet incur a lower computational cost. Software implementations of EEM and SFKEEM, including the developed parameters, are included in the conformer‐generation tool BALLOON , available free of charge at http://web.abo.fi/fak/mnf/bkf/research/johnson/software.php . © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

Protonmotive force: development of electrostatic drivers for synthetic molecular motors

Ferrocene has been investigated as a platform for developing protonmotive electrostatic drivers for molecular motors. When two 3-pyridine groups are substituted to the (rapidly rotating) cyclopentadienyl (Cp) rings of ferrocene, one on each Cp, it is shown that the (Cp) eclipsed, pi-stacked rotameric conformation is preferred both in solution and in the solid state. Upon quaternization of both of the pyridines substituents, either by protonation or by alkylation, it is shown that the preferred rotameric conformation is one where the pyridinium groups are rotated away from the fully pi-stacked conformation. Electrostatic calculations indicate that the rotation is caused by the electrostatic repulsion between the charges. Consistently, when the pi-stacking energy is increased pi-stacked population increases, and conversely when the electrostatic repulsion is increased pi-stacked population is decreased. This work serves to provide an approximate estimate of the amount of torque that the electrostatically driven ferrocene platform can generate when incorporated into a molecular motor. The overall conclusion is that the electrostatic interaction energy between dicationic ferrocene dipyridyl systems is similar to the pi-stacking interaction energy and, consequently, at least tricationic systems are required to fully uncouple the pi-stacked pyridine substituents.     

Accurate molecular electrostatic potentials based on modified PRDDO/M wave functions: II. Electrostatic potentials inside the molecular van der Waals envelope

In part I of this series, the PESP (parameterized electrostatic potential) method was described and applied to the calculation of electrostatic-potential-derived charges for a wide variety of organic and inorganic systems. Based on PRDDO/M wave functions and parameterized against ab initio MP2/6-31G** calculations, PESP is an order of magnitude faster than ab initio STO-3G calculations, while achieving a level of accuracy that rivals that of far more sophisticated ab initio methods. In this study, the application of the PESP method to the high potential regions of molecules containing H, C, N, O, F, P, S, Cl, and Br is described. For a collection of 48 molecules and 55 distinct lone pair minima, PESP yields the location and depth of lone pair minima to an average accuracy (relative to MP2/6-31G**) of 0.03 Å and 2.5 kcal/mol, respectively. Similarly, the location and well depths of minima in the π regions of organic molecules are calculated to an accuracy of 0.08 Å and 1.5 kcal/mol. PESP electrostatic potential maps are, in some cases, virtually indistinguishable from those obtained at the MP2/6-31G** level. © 1997 John Wiley & Sons, Inc. J Comput Chem 18 : 1682–1693, 1997     

Nonexistence of local maxima in molecular electrostatic potential maps

It has been rigorously established by means of classical electrostatic arguments, that molecular electrostatic potential maps are devoid of local maxima. This forms a generalization of the earlier works of Politzer and co-workers which were restricted to the case of atoms.     

Tailoring approach for exploring electron densities and electrostatic potentials of molecular crystals

Experimental and theoretical studies of electron densities and the corresponding derived entities such as electrostatic potentials have been the primary means of understanding the chemical nature and electronic properties of crystalline substances. Conventional crystal calculation methods such as the embedded cluster models are capable of performing calculations on small and medium-sized molecules, while periodic ab initio methods can treat crystals with up to 200 atoms per unit cell. A linear scaling method, viz. the molecular tailoring approach, has recently been developed for obtaining ab initio quality one-electron properties. In the present study, the molecular tailoring approach is employed to generate electron density, electrostatic potential and interaction density maps with the ibuprofen crystal as a test case. The interaction density and electrostatic potential maps produced in the present work succinctly bring out the actual crystalline environment around a given reference molecule by including the interactions with atoms in its neighborhood. The results obtained from the molecular tailoring approach may thus be expected to enhance our understanding of the environment in the crystalline material with reasonably small computational effort.Contribution to the Jacopo Tomasi Honorary Issue     

A computationally inexpensive modification of the point dipole electrostatic polarization model for molecular simulations

We present an approximation, which allows reduction of computational resources needed to explicitly incorporate electrostatic polarization into molecular simulations utilizing empirical force fields. The proposed method is employed to compute three-body energies of molecular complexes with dipolar electrostatic probes, gas-phase dimerization energies, and pure liquid properties for five systems that are important in biophysical and organic simulations-water, methanol, methylamine, methanethiol, and acetamide. In all the cases, the three-body energies agreed with high level ab initio data within 0.07 kcal/mol, dimerization energies-within 0.43 kcal/mol (except for the special case of the CH(3)SH), and computed heats of vaporization and densities differed from the experimental results by less than 2%. Moreover, because the presented method allows a significant reduction in computational cost, we were able to carry out the liquid-state calculations with Monte Carlo technique. Comparison with the full-scale point dipole method showed that the computational time was reduced by 3.5 to more than 20 times, depending on the system in hand and on the desired level of the full-scale model accuracy, while the difference in energetic results between the full-scale and the presented approximate model was not great in the most cases. Comparison with the nonpolarizable OPLS-AA force field for all the substances involved and with the polarizable POL3 and q90 models for water and methanol, respectively, demonstrates that the presented technique allows reduction of computational cost with no sacrifice of accuracy. We hope that the proposed method will be of benefit to research employing molecular modeling technique in the biophysical and physical organic chemistry areas.     

Site charge models for molecular electrostatic potentials of cycloalkanes and tetrahedrane

The molecular structures of cycloalkanes (from cyclopropane to cyclodecane) and tetrahedrane were optimized at the Hartree–Fock/6–31G** level and their molecular electric potentials (MEPs) were calculated using a geodesic grid. The MEPs were fitted using net atomic charges and several site charge models. The net atomic charge model gave very poor fits to the MEPs in every case. A model with additional methylene bisector charge sites, similar to one successfully used previously for linear alkanes, greatly improved the fits to the MEPs of these cycloalkanes. The MEPs of the highly strained molecules cyclopropane and tetrahedrane were further studied using ring center and displaced bond charge sites. The fitting of the MEP of cyclopropane was consistent with a banana bond model with asymmetrically displaced electron density in the C C bonds. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 579–585, 1999