Fast tools for calculation of atomic charges well suited for drug design1

Two novel approaches to construct empirical schemes for partial atomic charge calculation were proposed. The charge schemes possess important benefits. First, they produce both topologically symmetrical and environment dependent charges. Second, they can be parameterised to reasonably reproduce ab initio molecular electrostatic potential (MEP), which guarantees their successful use in molecular modelling. To validate the approaches, the parameters of the proposed charge schemes were fitted to best reproduce MEP simultaneously on grids around a set of 227 diverse organic compounds. The residual errors in MEP reproduction due to calculated atomic charges were compared to those due to charges from known charge schemes.     

Fast,efficient generation of high-quality atomic charges. AM1-BCC model: II. Parameterization and validation

We present the first global parameterization and validation of a novel charge model, called AM1-BCC, which quickly and efficiently generates high-quality atomic charges for computer simulations of organic molecules in polar media. The goal of the charge model is to produce atomic charges that emulate the HF/6-31G* electrostatic potential (ESP) of a molecule. Underlying electronic structure features, including formal charge and electron delocalization, are first captured by AM1 population charges; simple additive bond charge corrections (BCCs) are then applied to these AM1 atomic charges to produce the AM1-BCC charges. The parameterization of BCCs was carried out by fitting to the HF/6-31G* ESP of a training set of >2700 molecules. Most organic functional groups and their combinations were sampled, as well as an extensive variety of cyclic and fused bicyclic heteroaryl systems. The resulting BCC parameters allow the AM1-BCC charging scheme to handle virtually all types of organic compounds listed in The Merck Index and the NCI Database. Validation of the model was done through comparisons of hydrogen-bonded dimer energies and relative free energies of solvation using AM1-BCC charges in conjunction with the 1994 Cornell et al. forcefield for AMBER.(13) Homo- and hetero-dimer hydrogen-bond energies of a diverse set of organic molecules were reproduced to within 0.95 kcal/mol RMS deviation from the ab initio values, and for DNA dimers the energies were within 0.9 kcal/mol RMS deviation from ab initio values. The calculated relative free energies of solvation for a diverse set of monofunctional isosteres were reproduced to within 0.69 kcal/mol of experiment. In all these validation tests, AMBER with the AM1-BCC charge model maintained a correlation coefficient above 0.96. Thus, the parameters presented here for use with the AM1-BCC method present a fast, accurate, and robust alternative to HF/6-31G* ESP-fit charges for general use with the AMBER force field in computer simulations involving organic small molecules.     

Off‐atomic site charges in some anions,metal cations,and complexes: Significance for electrostatic properties and binding

Electronic structures and properties of several anions, metal cations, and their complexes with neutral molecules were investigated at the HF/6‐31G** and B3LYP/6‐31G** levels of theory. Charges shifted from atomic sites due to atomic orbital hybridization called hybridization displacement charges (HDC) were investigated in detail. It has been found that many components of HDC are associated with each atom of ion that are shifted from the atomic sites, those associated with metal cations being shifted by large distances as found previously in electrically neutral systems. It is shown that atomic orbitals are appreciably rehybridized in going from neutral molecules to anions and cations. Molecular dipole moments and surface molecular electrostatic potentials (MEP) are obtained satisfactorily using HDC for the various types of species mentioned above. In the OH^?? H₂O complex, reversal of direction of shift of an HDC component associated with the hydrogen atom of H₂O involved in hydrogen bonding, indicates that the hydrogen bond between OH^? and H₂O would have some covalent character. Other atomic site‐based point charge models cannot provide such information about the nature of bonding. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem 2007     

Molecule‐specific determination of atomic polarizabilities with the polarizable atomic multipole model

Recently, many polarizable force fields have been devised to describe induction effects between molecules. In popular polarizable models based on induced dipole moments, atomic polarizabilities are the essential parameters and should be derived carefully. Here, we present a parameterization scheme for atomic polarizabilities using a minimization target function containing both molecular and atomic information. The main idea is to adopt reference data only from quantum chemical calculations, to perform atomic polarizability parameterizations even when relevant experimental data are scarce as in the case of electronically excited molecules. Specifically, our scheme assigns the atomic polarizabilities of any given molecule in such a way that its molecular polarizability tensor is well reproduced. We show that our scheme successfully works for various molecules in mimicking dipole responses not only in ground states but also in valence excited states. The electrostatic potential around a molecule with an externally perturbing nearby charge also exhibits a near‐quantitative agreement with the reference data from quantum chemical calculations. The limitation of the model with isotropic atoms is also discussed to examine the scope of its applicability. © 2012 Wiley Periodicals, Inc.     

On the definition of the atomic charge. Relationship between 13C NMR chemical shifts,dipole moments,and charges in saturated hydrocarbons

The problem of defining a reliable quantum mechanical charge by comparison with one-electron properties is analyzed, and it is stressed that properties involving the virtual space are not suited to that end. Particular attention is devoted to the relationship between charges and chemical shifts for the case of saturated hydrocarbons. A simple explanation of the Grant and Paul α effect is suggested, which can also account for the modified population analysis proposed by Fliszár. Moreover the vexata quaestio of the direction of the C H bond dipole moment has been reexamined. The awkward theoretical prediction (C⁺ H⁻) can be reconciled with the one based on experimental data and electronegativities (C⁻ H⁺) if one considers that the former is determined by an hydridization contribution to the dipole moment, which tend to cancel in a summation over all the bonds formed by each atom. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 68: 201–210, 1998     

Determination of side‐chain‐rotamer and side‐chain and backbone virtual‐bond‐stretching potentials of mean force from AM1 energy surfaces of terminally‐blocked amino‐acid residues,for coarse‐grained simulations of protein structure and folding. I. The method

In this and the accompanying article, we report the development of new physics‐based side‐chain‐rotamer and virtual‐bond‐deformation potentials which now replace the respective statistical potentials used so far in our physics‐based united‐reside UNRES force field for large‐scale simulations of protein structure and dynamics. In this article, we describe the methodology for determining the corresponding potentials of mean force (PMF's) from the energy surfaces of terminally‐blocked amino‐acid residues calculated with the AM1 quantum‐mechanical semiempirical method. The approach is based on minimization of the AM1 energy for fixed values of the angles λ for rotation of the peptide groups about the C^α ··· C^α virtual bonds, and for fixed values of the side‐chain dihedral angles χ, which formed a multidimensional grid. A harmonic‐approximation approach was developed to extrapolate from the energy at a given grid point to other points of the conformational space to compute the respective contributions to the PMF. To test the applicability of the harmonic approximation, the rotamer PMF's of alanine and valine obtained with this approach have been compared with those obtained by using a Metropolis Monte Carlo method. The PMF surfaces computed with the harmonic approximation are more rugged and have more pronounced minima than the MC‐calculated surfaces but the harmonic‐approximation‐and MC‐calculated PMF values are linearly correlated. The potentials derived with the harmonic approximation are, therefore, appropriate for UNRES for which the weights (scaling factors) of the energy terms are determined by force‐field optimization for foldability. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

Ultraviolet grafting of methacrylic acid and acrylic acid on high‐density polyethylene in different solvents and the wettability of grafted high‐density polyethylene. I. Grafting

Methacrylic acid (MAA) and acrylic acid (AA) were grafted onto high‐density polyethylene (PE) with UV initiation and a range of solvents. With acetone as the solvent, MAA was more easily grafted onto PE when the photoinitiator benzophenone was precoated on PE than when it was dissolved in the monomer solution. The grafting was faster in aliphatic solvents than in polar solvents or a UV‐adsorbing aromatic solvent (toluene). Acetone itself could initiate the photografting of both MAA and AA onto PE when it was mixed with water. The extent of grafting of MAA onto PE showed a maximum when there was about 40% acetone in the mixture. For AA, when the acetone/water concentration was 10%, the extent of grafting increased rapidly with the irradiation time. At higher acetone concentrations, the extent of grafting was low. Atomic force microscopy images showed that the surface topography of PE grafted with MAA in acetone/water was quite different from that obtained when the grafting was performed in other organic solvents. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 253–262, 2004     

Building up 1‐D, 2‐D,and 3‐D Polyiodide Frameworks by Finely Tuning the Size of Aryls on Ar‐S‐TTF in the Charge‐Transfer (CT) Complexes of Ar‐S‐TTFs and Iodine

The arylthio‐substituted tetrathiafulvalenes (Ar‐S‐TTFs) are electron donors having three reversible states, neutral, cation radical, and dication. The charge‐transfer (CT) between Ar‐S‐TTFs ( TTF1 — TTF3 ) and iodine (I₂) is reported herein. TTF1 — TTF3 show the CT with I₂ in the CH₂Cl₂ solution, but they are not completely converted into cation radical state. In CT complexes of TTF1 — TTF3 with I₂, the charged states of Ar‐S‐TTFs are distinct from those in solution. TTF1 is at cation radical state, and TTF2 — TTF3 are oxidized to dication. The iodine components in complexes show various structures including 1‐D chain of V‐shaped (I₅)^–, and 2‐D and 3‐D iodine networks composed of I₂ and (I₃)^–.     

FFLUX: Transferability of polarizable machine‐learned electrostatics in peptide chains

The fully polarizable, multipolar, and atomistic force field protein FFLUX is being built from machine learning (i.e., kriging) models, each of which predicts an atomic property. Each atom of a given protein geometry needs to be assigned such a kriging model. Such a knowledgeable atom needs to be informed about a sufficiently large environment around it. The resulting complexity can be tackled by collecting the 20 natural amino acids into a few groups. Using substituted deca‐alanines, we present the proof‐of‐concept that a given atom's charge can be modeled by a few kriging models only. © 2017 Wiley Periodicals, Inc.     

Biotransformation,spectroscopic investigation,crystal structure and electrostatic properties of 3,7α‐dihydroxyestra‐1,3,5(10)‐trien‐17‐one monohydrate studied using transferred electron‐density parameters

The biologically transformed product of estradiol valerate, namely 3,7α‐dihydroxyestra‐1,3,5(10)‐trien‐17‐one monohydrate, C₁₈H₂₂O₃·H₂O, has been investigated using UV–Vis, IR, ¹H and ¹³C NMR spectroscopic techniques, as well as by mass spectrometric analysis. Its crystal structure was determined using single‐crystal X‐ray diffraction based on data collected at 100 K. The structure was refined using the independent atom model (IAM) and the transferred electron‐density parameters from the ELMAM2 database. The structure is stabilized by a network of hydrogen bonds and van der Waals interactions. The topology of the hydrogen bonds has been analyzed by the Bader theory of `Atoms in Molecules' framework. The molecular electrostatic potential for the transferred multipolar atom model reveals an asymmetric character of the charge distribution across the molecule due to a substantial charge delocalization within the molecule. The molecular dipole moment was also calculated, which shows that the molecule has a strongly polar character.     

The dual role of halogen,chalcogen, and pnictogen atoms as Lewis acid and base: Triangular XBr:SHX:PH2X complexes (X = F,Cl, Br,CN, NC,OH, NH2, and OCH3)

Using ab initio calculations, we have investigated the possibility of formation of triangular XBr:SHX:PH₂X complexes, where X = F, Cl, Br, CN, NC, OH, NH₂, and OCH₃. These complexes are formed through the interaction of a positive electrostatic potential region (σ‐hole) on a molecule with the negative region in another one. The results show that the combined halogen, chalcogen, and pnictogen interactions can give rise to stable cyclic structures. The interaction energies of these complexes span over a wide range, from ?3.55 to ?24.93 kcal/mol. Nice quadratic correlations are found between the interaction energies and binding distances in the trimers. To understand the nature of the interactions in these complexes, molecular electrostatic potential and quantum theory of atoms in molecule analyses are performed. © 2015 Wiley Periodicals, Inc.     

Accurate molecular electrostatic potentials based on modified PRDDO/M wave functions: III. Extension of the PESP method for calculation of electrostatic potential-derived atomic charges to compounds containing Li+, Na+, Mg2+, K+, Ca2+, Zn2+, and I

The PESP (Parameterized ElectroStatic Potential) method for calculating molecular electrostatic potentials, previously parameterized for H, C, N, O, F, P, S, Cl, and Br, is extended to molecules containing Li⁺, Na⁺, Mg²⁺, K⁺, Ca²⁺, Zn²⁺, and I. For a collection of 166 molecules containing 1668 atoms with at least one metal or iodine atom, PESP achieves an average absolute deviation in electrostatic potential-derived atomic charges of 0.042e⁻ compared with ab initio MP2/6-31G** calculations, with a correlation coefficient of 0.996. For a larger data set, consisting of 311 molecules encompassing all of the 16 elements just listed (2488 total atoms), PESP achieves an average absolute deviation of 0.040e⁻ and a correlation coefficient of 0.995. PESP calculations are an order of magnitude faster than the simplest ab initio method (STO-3G) on large molecules, while achieving a level of accuracy that rivals much more elaborate ab initio methods. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 1456–1469, 1998     

Computational study of sulfoxides of thiacyclohexane, 4‐silathiacyclohexane, 4‐fluoro‐4‐silathiacyclohexane,and 4,4‐difluoro‐4‐silathiacyclohexane: Relative energies of conformations and sulfinyl oxygen stabilized pentacoordinate silicon in boat and twist structures

Second‐order Møller‐Plesset theory (MP2) has been used to calculate the equilibrium geometries and relative energies of the chair, 1,4‐twist, 2,5‐twist, 1,4‐boat, and 2,5‐boat conformations of thiacyclohexane 1‐oxide (tetrahydro‐2H‐thiopyran 1‐oxide), 4‐silathiacyclohexane 1‐oxide, cis‐ and trans‐4‐fluoro‐4‐silathiacyclohexane 1‐oxide, and 4,4‐difluoro‐4‐silathiacyclohexane 1‐oxide. At the MP2/6‐311+G(d,p) level of theory, the chair conformer of axial thiacyclohexane 1‐oxide is 0.99, 5.61, 5.91, 8.57, and 7.43 kcal/mol more stable (ΔE) than its respective equatorial chair, 1,4‐twist, and 2,5‐twist conformers and 1,4‐boat and 2,5‐boat transition states. The chair conformer of equatorial thiacyclohexane 1‐oxide is 4.62, 6.31, 7.56, and 7.26 kcal/mol more stable (ΔE) than its respective 1,4‐twist and 2,5‐twist conformers and 1,4‐boat and 2,5‐boat transition states. The chair conformer of axial 4‐silathiacyclohexane 1‐oxide is 1.79, 4.26, 3.85, and 5.71 kcal/mol more stable (ΔE) than its respective equatorial chair, 1,4‐twist, and 2,5‐twist conformers and 2,5‐boat transition state. The 2,5‐twist conformer of axial 4‐silathiacyclohexane 1‐oxide is stabilized by a transannular interaction between the sulfinyl oxygen and silicon, to give trigonal bipyramidal geometry at silicon. The chair conformer of equatorial 4‐silathiacyclohexane 1‐oxide is 2.47, 7.90, and 8.09 kcal/mol more stable (ΔE) than its respective 1,4‐twist, and 2,5‐twist conformers and 2,5‐boat transition state. The chair conformer of axial cis‐4‐fluoro‐4‐silathiacyclohexane 1‐oxide is 4.18 and 5.70 kcal/mol more stable than its 1,4‐twist conformer and 2,5‐boat transition state and 1.51 kcal/mol more stable than the chair conformer of equatorial cis‐4‐fluoro‐4‐silathiacyclohexane 1‐oxide. The chair conformer of axial trans‐4‐fluoro‐4‐silathiacyclohexane 1‐oxide is 5.02 and 6.11 kcal/mol more stable than its respective 1,4‐twist conformer and 2,5‐boat transition state, but is less stable than its 2,5‐twist conformer (ΔE = ?1.77 kcal/mol) and 1,4‐boat transition state (ΔE = ?1.65 kcal/mol). The 2,5‐twist conformer and 1,4‐boat conformer of axial trans‐4‐fluoro‐4‐silathiacyclohexane 1‐oxide are stabilized by intramolecular coordination of the sulfinyl oxygen with silicon that results in trigonal bipyramidal geometry at silicon. The chair conformer of axial 4,4‐difluoro‐4‐silathiacyclohexane 1‐oxide is 3.02, 5.16, 0.90, and 6.21 kcal/mol more stable (ΔE) than its respective equatorial chair, 1,4‐twist, and 1,4‐boat conformers and 2,5‐boat transition state. The 1,4‐boat conformer of axial 4,4‐difluoro‐4‐silathiacyclohexane 1‐oxide is stabilized by a transannular coordination of the sulfinyl oxygen with silicon that results in a trigonal bipyramidal geometry at silicon. The relative energies of the conformers and transition states are discussed in terms of hyperconjugation, orbital interactions, nonbonded interactions, and intramolecular sulfinyl oxygen–silicon coordination. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Synthesis,structural elucidation,characterization and theoretical DFT study of 1‐(o‐tolyl)biguanidium chloride

The structure of the new salt 1‐(o‐tolyl)biguanidium chloride, C₉H₁₄N₅⁺·Cl^?, has been determined by single‐crystal X‐ray diffraction. The salt crystallizes in the monoclinic space group C2/c. In this structure, the chloride and biguanidium hydrophilic ions are mostly connected to each other via N—H…N and N—H…Cl hydrogen bonds to form layers parallel to the ab plane around y = and y = . The 2‐methylbenzyl groups form layers between these layers around y = 0 and y = , with the methyl group forming C—H…π interactions with the aromatic ring. Intermolecular interactions on the Hirshfeld surface were investigated in terms of contact enrichment and electrostatic energy, and confirm the role of strong hydrogen bonds along with hydrophobic interactions. A correlation between electrostatic energy and contact enrichment is found only for the strongly attractive (N—H…Cl^?) and repulsive contacts. Electrostatic energies between ions reveal that the interacting biguanidium cation pairs are repulsive and that the crystal is maintained by attractive cation…Cl^? dimers. The vibrational absorption bands were identified by IR spectroscopy.