Conformational dependence of electrostatic potential-derived charges: Studies of the fitting procedure

Atomic monopole “point charges” are routinely determined through a least squares fit to molecular electrostatic potentials [potential-derived (PD) charges]. Previously, it has been shown that these charges vary with variation in molecular conformation. Also, it has been observed that these swings in charges are highly correlated between neighboring atoms. Here, we examine the least squares variance–covariance data matrices for a set of data in the literature and find further indications of high colinearity within the data. These colinearities effectively reduce the dimensionality of the data to a value well below the number of atoms in the molecules. This suggests that the data is not of sufficient dimensionality to support calculation of the charges for all of the atoms in a statistically significant way. We experiment with fixing the charges of atoms whose PD charges reflect large errors in the fit. The resulting estimates of fit of the remaining charges are little degraded from the estimates of fit when the charges of all of the atoms are fit. In addition, the charges that are fit take what would be considered more reasonable and “chemically intuitive” values, often of smaller magnitude. Although most of the free charges continue to vary with molecular conformation, their range is no larger than when all charges were fit and, in some cases, the ranges of the charges for the fit atoms is actually reduced over those that are found when all of the atoms take part in the fitting procedure. The errors of fit are lower and the unconstrained charges appear more reasonable when more chemically “reasonable” charges are used for the fixed values. This suggests that in many cases charges are transferable between molecules. Further, it shows a way to justifiably reduce the large fluctuations in PD charges that occur with variations in conformation. © 1993 John Wiley & Sons, Inc.     

Conformational sensitivity of polyether macrocycles to electrostatic potential: Partial atomic charges,molecular mechanics,and conformational prediction

Molecular recognition (whether by enzymes, the immune system, or chelating ligands) depends critically on molecular conformation. Molecular mechanics predicts energetically favorable molecular conformations by locating low energy conformations using an empirical fit of molecular potential energy as a function of internal coordinates. Molecular mechanics analysis of 18-crown-6 demonstrates that the nonbonded term (primarily the electrostatic part) is the largest contributor to the conformational energy. Nevertheless, common methods of treating the electrostatic interaction for 18-crown-6 yield inconsistent values for conformational energies partly because partial charges assigned to each atom can change with conformation due to through-space inductive effects which are not considered in most molecular mechanics programs. Similar findings from several other groups are reviewed to support our conclusions. We argue for care and caution in predicting conformational preferences of molecules with two or more highly polar atoms. We also discuss the desirability of using an empirical method of partial charge determination such as the charge equilibration algorithm of Rappé and Goddard (or a suitable generalization which includes polarization) as a method of including these effects in molecular mechanics and molecular dynamics calculations.     

Restrained point-charge models for disaccharides

Various methods for deriving atomic partial charges from the quantum chemical electrostatic potential and moments have been tested for the sucrose molecule. We show that if no further information is used, the charges on some carbon atoms become large and charge patterns involving these atoms are badly determined and poorly transferable. Adding lone-pairs on the ether oxygen atoms or dividing the molecule into smaller fragments did not cure the instabilities. We develop a method, CHELP-BOW0, that restrains charges toward zero with different weights for different atoms. These harmonic restraints preserve the linear form of the least-squares equations, which are solved in a single step using singular-value decomposition. CHELP-BOW0 improves the chemical transferability of the charges compared to unrestrained methods, and slightly improves their conformational transferability. It introduces a modest degradation of the fit compared to unrestrained CHELP-BOW (mean average deviation of the potential 0.00016 vs. 0.00010 a.u.). A second new method, CHELP-BOWC, avoids the need for restraints by including several conformations in the fit, weighting each according to its estimated energy in solution. CHELP-BOWC charges are more transferable than CHELP-BOW or CHELP-BOW0 charges to conformations not included in the training set. Restraints to zero charge do not further improve transferability of the CHELP-BOWC charges. We, therefore, recommend CHELP-BOW charges for rigid molecules and CHELP-BOWC charges for flexible molecules.     

Solvated ensemble averaging in the calculation of partial atomic charges

In the calculation of partial atomic charges, for use in molecular mechanics or dynamics simulations, it is common practice to select only a single conformation for the molecule of interest. For molecules that contain rotatable bonds, it is preferable to compute the charges from several relevant conformations. We present here results from a charge derivation protocol that determines the partial charges by averaging charges computed for conformations selected from explicitly solvated MD simulations, performed under periodic boundary conditions. This approach leads to partial charges that are weighted by a realistic population of conformations and that are suitable for condensed phase simulations. This protocol can, in principle, be applied to any class of molecule and to nonaqueous solvation. Carbohydrates contain numerous hydroxyl groups that exist in an ensemble of orientations in solution, and in this report we apply ensemble averaging to a series of methyl glycosides. We report the extent to which ensemble averaging leads to charge convergence among the various monosaccharides and among the constituent atoms within a given monosaccharide. Due to the large number of conformations (200) in our ensembles, we are able to compute statistically relevant standard deviations for the partial charges. An analysis of the standard deviations allows us to assess the extent to which equivalent atom types may, nevertheless, require unique partial charges. The configurations of the hydroxyl groups exert considerable influence on internal energies, and the limits of ensemble averaged charges are discussed in terms of these properties.     

Conformational dependence of the electrostatic potential-derived charges of dopamine: Ramifications in molecular mechanics force field calculations in the gas phase and in aqueous solution

The electrostatic potential-derived charges for the catecholamine neurotransmitter dopamine were calculated at the STO-3G and 6-31G* basis sets for six different molecular conformations. The degree of variance of the charges with changing conformations was examined. The 6-31G* basis set produced charges that were more sensitive to changes in conformation than those derived from the STO-3G electrostatic potentials. The implication of the charge variations in molecular mechanics calculations was also investigated. The molecular mechanics results in the gas phase exhibited a variance depending upon the charge set used. The force field calculations varied much less when aqueous solvation was included in the calculations through a continuum model. © 1993 John Wiley & Sons, Inc.     

Computational investigation and hydrogen/deuterium exchange of the fixed charge derivative tris(2,4,6-Trimethoxyphenyl) phosphonium: Implications for the aspartic acid cleavage mechanism

Aspartic acid (Asp)-containing peptides with the fixed charge derivative tris(2,4,6trimethoxyphenyl) phosphonium (tTMP-P+) were explored computationally and experimentally by hydrogen/deuterium (H/D) exchange and by fragmentation studies to probe the phenomenon of selective cleavage C-terminal to Asp in the absence of a "mobile" proton. Ab initio modeling of the tTMP-P+ electrostatic potential shows that the positive charge is distributed on the phosphonium group and therefore is not initiating or directing fragmentation as would a "mobile" proton. Geometry optimizations and vibrational analyses of different Asp conformations show that the Asp structure with a hydrogen bond between the side-chain hydroxy and backbone carbonyl lies 2.8 kcal/mol above the lowest energy conformer. In reactions with D2O, the phosphonium-derived doubly charged peptide (H+)P+LDIFSDF rapidly exchanges all 12 of its exchangeable hydrogens for deuterium and also displays a nonexchanging population. With no added proton, P+LDIFSDF exchanges a maximum of 4 of 11 exchangeable hydrogens for deuterium. No exchange is observed when all acidic groups are converted to the corresponding methyl esters. Together, these H/D exchange results indicate that the acidic hydrogens are "mobile locally" because they are able to participate in exchange even in the absence of an added proton. Fragmentation of two distinct (H+)P+LDIFSDF ion populations shows that the nonexchanging population displays selective cleavage, whereas the exchanging population fragments more evenly across the peptide backbone. This result indicates that H/D exchange can sometimes distinguish between and provide a means of separation of different protonation motifs and that these protonation motifs can have an effect on the fragmentation.     

Conformational analysis of chlorocholine analogues

The high-resolution proton magnetic resonance spectra of the methylene groups of 2-chloroethyl trimethyl ammonium chloride (I) and 2-chloroethyl dimethyl ammonium chloride (II) were studied by iterative computer calculation. From the values of the spectral parameter L it is concluded that in the case of compound (I) the enthalpy difference between the antiperiplanar and the synclinal conformers is very low, probably, emphasis lies on the antiperiplanar conformation. Compound (II) exists in a dominant synclinal conformation. PCILO calculations of 2-chloroethyl trimethyl ammonium yield the antiperiplanar conformation as the most stable one in agreement with experiment. The energy difference between the antiperiplanar and the syn/anticlinal conformation is 0.7 kcal mole^?1. 2-Chloroethyl dimethyl ammonium, 2-chloroethyl methyl ammonium and 2-chloroethyl ammonium in our PCILO calculations exist in a predominant synclinal conformation. The calculated charge distributions demonstrate that the quaternary nitrogen atom is approximately neutral, the “positive” charge is distributed among the methyl groups and hydrogen atoms attached to the nitrogen atom.     

Complementary molecular orbital investigations on the conformation of choline derivatives

Quantum-mechanical computations by the PCILO method, applied previously to the study of the conformational properties of acetylcholine and its derivatives modified in the central part of this molecule, are extended to modifications involving its cationic head and its ester terminal. The replacement of the methyl groups of the cationic head by hydrogens or ethyl groups leads to a steep decline in parasympathomimetic activity. It is shown that the triethyl derivative conserves the gauche form as the most stable one. The redistribution of the electronic charges at the onium group implies, however, a transition from an ionic to a hydrophobic binding. The replacement of the methyls by two or three hydrogens leads to a different preferred gauche-gauche conformation. The replacement of the methyl group at the ester terminal by a phenyl ring enables a comparison with the conformational properties of local anesthetics. The study brings about evidence, substantiated by NMR spectroscopy, that acetylcholine analogs and protonated local anesthetics are conformationally similar. Choline ethers also show a general preference for a gauche conformation. Nevertheless, biological studies do not indicate a constant correlation between conformation and biological potency. Conformational analogies or discrepancies alone cannot thus account for the fine details of the biological activity which must depend also on the electronic structure.This work was supported by the A.T.P. N A 655-2303 of the C.N.R.S.     

An Electrostatic Bond Energy Model for Enthalpies of Formation of Chloroalkanes in Gaseous States

An electrostatic bond energy model is formulated to fit the enthalpies of formation and dipole moments of the alkanes and chloroalkanes. In this model, the charge distributions are calculated by an electrostatic approach similar to the "MSE" method, and the enthalpy of formation of a molecule is the sum of the bond energy terms plus the electrostatic energy of the interactions between the charges on all atoms. All parameters of this model are obtained by parameterization. The calculated dipole moments for 13 chloroalkanes and enthalpies of formation for 19 alkanes and non-geminal chloroalkanes agree with the determined values very well. To calculate the enthalpies of formation of geminal chloroalkanes, a correction mainly attributed to the van der Waals interactions in the geminal substituted group, about 24 kJ/mol per pair of geminal chlorine atoms, is introduced.     

A generalization of the charge equilibration method for nonmetallic materials

Assigning effective atomic charges that properly reproduce the electrostatic fields of molecules is a crucial step in the construction of accurate interatomic potentials. We propose a new approach to calculate these charges, which as previous approaches are, is based on the idea of charge equilibration. However, we only allow charge to flow between covalently bonded neighbors by using the concept of so-called split charges. The semiempirical fit parameters in our approach do not only reflect atomic properties (electronegativity and atomic hardness) but also bond-dependent properties. The new method contains two popular but hitherto disjunct approaches as limiting cases. We apply our methodology to a set of molecules containing the elements silicon, carbon, oxygen, and hydrogen. Effective charges derived from electrostatic potential surfaces can be predicted more than twice as accurately as with previous works, at the expense of one additional fit parameter per bond type controlling the polarizability between two bonded atoms. Additional bond-type parameters can be introduced, but barely improve the results. An increase in accuracy of only 30% over existing techniques is achieved when predicting Mulliken charges. However, this could be improved with additional bond-type parameters.     

Molecular modeling of sigma receptor ligands: A model of binding based on conformational and electrostatic considerations

We have performed molecular modeling studies on four representative sigma receptor specific ligands, (+)haloperidol, (+)3-PPP, (+)pentazocine and progesterone, to develop a model for sigma receptor-ligand binding. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Based on the complementarity of the conformational and electrostatic properties of the ligands, a model of binding has been proposed which shows that the four ligands can fit a common receptor sit. Unlike the binding model for haloperidol that was previously proposed by Manallack and Andrews, our model binds haloperidol in the gauche conformation. The first site binds the fluorophenyl group and the second site the lone pair of the piperidine nitrogen. This pharmacophore can be presented by (+)3-PPP and (+)pentazocine, but for progesterone the binding model requires the ring junction of the cyclohexenyl ring A and ring B to fit the fluorophenyl region, while the lone pair of the acetylcarbonyl oxygen at ring D emulates the nitrogen lone pair of the piperidine ring. Calculations were performed using RCG5 for generating conformations, molecular mechanics for calculating steric energies, quantum mechanical methods for generating charges, and ARCHEM for calculating electrostatic potentials on the Van der Waals surface.     

Theoretical and experimental studies of enflurane. Infrared spectra in solution, in low-temperature argon matrix and blue shifts resulting from dimerization

Theoretical studies are performed on enflurane (CHFCl-CF(2)-O-CHF(2)) to investigate the conformational properties and vibrational spectra. Calculations are carried out at the B3LYP/6-31G(d) level along with a natural bond orbital (NBO) analysis. Experimental infrared spectra are investigated in carbon tetrachloride solution at room temperature and in argon matrix at 12 K. In agreement with previously reported data (Pfeiffer, A.; Mack, H.-G.; Oberhammer, H. J. Am. Chem. Soc. 1998, 120, 6384), it is shown that the four most stable conformers possess a trans configuration of the C-C-O-C skeleton and a gauche orientation of the CHF(2) group (with respect to the central C-O bond). These conformations are favored by electrostatic interaction between the H atom of the CHF(2) group and the F atoms of the central CF(2) group. Hyperconjugation effects from the O lone pairs to the antibonding orbitals of the neighboring C-H and C-F bonds also contribute to the stability of the four conformers. The vibrational frequencies, infrared intensities, and potential energy distributions are calculated at the same level of theory for the most stable conformers. On the basis of the theoretical results, these conformers are identified in an argon matrix. The influence of the concentration on the nu(CH) vibrations suggests the formations of higher aggregates in solution. Theoretical calculations are carried out on the enflurane dimer. The results show that the dimer is formed between two enflurane conformers having the largest stability. The dimer has an asymmetric cyclic structure, the two enflurane molecules being held together by two nonequivalent C-H...F hydrogen bonds, the C-H bond of the CHFCl group acting as a proton donor, and one of the F atoms of the CHF(2) groups acting as a proton acceptor. The theory predicts a contraction of 0.0014-0.0025 A of the two CH bonds involved in the interaction along with a blue shift of 30-38 cm(-1) of the corresponding nu(C-H) bands, in good agreement with the blue shifts of 35-39 cm(-1) observed in an argon matrix.     

Theoretical study of morphine and heroin: Conformational study in gas phase and aqueous solution and electron distribution analysis

The conformational preferences of morphine and heroin were studied in gas phase and with inclusion of solvent effects. At 298.15 K, three conformers are significant for isolated morphine, all of them displaying antiperiplanar arrangement for the C2? C3? O? H unit, and there is only one significantly populated conformer for heroin. Quantum theory of atoms in molecules analysis of the electron density in their most populated conformers in gas phase indicates that the positive charge is shared among the amino hydrogen, those hydrogens of the methylamino group, and all of the hydrogens attached to the bridgehead carbons. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2472–2482, 2010     

Fast assignment of accurate partial atomic charges: an electronegativity equalization method that accounts for alternate resonance forms

A fast, accurate method of assigning partial atomic charges is described. The method is based upon the concept of electronegativity equalization and is parametrized to fit electrostatic potentials obtained from ab initio quantum calculations. A novel algorithm for identifying alternate resonance forms is used to ensure that chemically equivalent atoms are assigned equal charges. The resulting charges are independent of conformation, yield good agreement with ab initio electrostatic potentials, and are similar to standard force field charges for common biochemical components. The method is broadly parametrized and generates charges for a drug-like compound in about 0.45 s on a 2.26 GHz Pentium 4 PC. It should thus be useful in a range of applications, such as molecular design and QSAR. The resonance algorithm is expected to have additional applications, such as in atom-typing and detection of molecular symmetry.     

Quantum chemical analysis of the energetics of the anti and gauche conformers of ethanol

Ethanol displays two stable conformers, the classic anti (or trans) form and a gauche conformation in which the hydroxyl hydrogen points toward one of the methyl hydrogens. Surprisingly, the two forms have nearly equal energies, and in the vapor phase the gauche form predominates because of its twofold degeneracy. An analysis of the energetics of these conformers based on natural bond orbital analysis helps to explain the apparently anomalous near degeneracy of these conformers.     

Recoordination of a metal ion in the cavity of a crown compound: a theoretical study. 1. Conformers of arylazacrown ethers and their complexes with Ca2+ cation

Photoinduced recoordination of Ca²⁺ complexes of the photochromic azacrown ethers is studied by the density functional method. The study included model arylazacrown ethers containing various acceptor groups in the aromatic ring in the para position to the azacrown ether moiety and a real azacrown-containing styryl dye. It is found that both free azacrown ethers and their complexes can adopt two types of conformations: (1) axial conformations, in which the aromatic ring axis passing through the crown ether nitrogen N_cr and the opposite atom of the aromatic ring is perpendicular to the root-mean-square (RMS) plane of the crown ether (least-squares fitted plane for all the crown ether atoms), and (2) equatorial conformations, in which the aromatic ring axis only slightly deflects from the RMS plane of the crown ether. In the equatorial conformers, the metal cation is coordinated only to the O atoms of the azacrown ether cycle, the metal—nitrogen bond is broken, and N_cr is conjugated with the aromatic ring. In the axial conformers, the metal cation is additionally coordinated to N_cr. It is found that the presence of an acceptor group bearing a formal positive charge decreases the relative energy of the equatorial conformer and favors metal—nitrogen bond dissociation, which results in the recoordination of the metal cation. However, a long distance between the charged group and N_cr has the reverse effect. The photoinduced recoordination observed in the alkaline-earth metal complexes of the photochromic azacrown ethers is explained by the transitions between the axial and equatorial conformers facilitated by the charge transfer in the excited state of the complex.     

The Shapes of Sulfonamides: A Rotational Spectroscopy Study

Benzenesulfonamides are a class of molecules of extreme interest in the biochemical field because many of them are active against a variety of diseases. In this work, the pharmacophoric group benzensulfonamide, its derivatives para-toluensulfonamide and ortho-toluensulfonamide, and the bioactive molecule sulfanilamide, were investigated using rotational spectroscopy to determine their conformations and the influence of different substituents on their structures. For all species, the hyperfine structure due to the ¹⁴N atom was analyzed, and this provided crucial information for the unambiguous identification of the observed conformation of all molecules. In addition, for ortho-toluensulfonamide, the vibration–rotation hyperfine structure related to the methyl torsion was analyzed, and the methyl group rotation barrier was determined. For benzensulfonamide, partial r_S and r₀ structures were established from the experimental rotational constants of the parent and two deuterated isotopic species. In all compounds except ortho-toluensulfonamide, the amino group of the sulfonamide group lies perpendicular to the benzene plane with the aminic hydrogens eclipsing the oxygen atoms. In ortho-toluensulfonamide, where weak attractive interactions occur between the nitrogen lone pair and the methyl hydrogen atoms, the amino group lies in a gauche orientation, retaining the eclipsed configuration with respect to the SO₂ frame. A comparison of the geometrical arrangements found in the PDB database allowed us to understand that the bioactive conformations are different from those found in isolated conditions. The conformations within the receptor are reached with an energy cost, which is balanced by the interactions established in the receptor.     

Dodecatwistarene Imides with Zigzag-Twisted Conformation for Organic Electronics

1D nonplanar graphene nanoribbons generally have three possible conformers: helical, zigzag, and mixed conformations. Now, a kind of 1D nonplanar graphene nanoribbon, namely dodecatwistarene imides featuring twelve linearly fused benzene rings, was obtained by bottom-up synthesis of palladium-catalyzed Stille coupling and C−H activation. Single-crystal X-ray diffraction analyses revealed that it displays a zigzag-twisted conformation caused by steric hindrance between imide groups and neighboring annulated benzene rings with the pendulum angle of 53°. This conformation is very stable and could not convert into other conformations even when heated up to 250 °C for 6 h. Despite of the highly twisted topology, organic field-effect transistor based on it exhibits electron mobility up to 1.5 cm² V⁻¹ s⁻¹ after annealing.     

Steric and electronic effects on the conformations of n-butane derivatives with trichlorosilyl, silyl and trichloromethyl groups

The molecular structure and conformation of 1,1,1,4,4,4-hexachloro-1,4-disilabutane in the gas-phase have been determined by electron diffraction and computational methods. The lowest-energy conformation has the trichlorosilyl groups anti to one another. The gauche conformation also has a shallow potential minimum, but lies about 19 kJ mol-1 above the anti form. Calculations on related butane derivatives, in which terminal methyl groups have been replaced by CCl3, SiH3 and SiCl3 groups, reveal that the conformational preferences are primarily caused by steric interactions between the terminal groups, and that it is the presence of chlorine atoms that destabilises gauche conformations. The electronegativity of the chlorine atoms has only small effects, mainly limited to the SiCl bond lengths.