Electric field-derived point charges to mimic the electrostatics in molecular crystals

Because of the way the electrostatic potential is defined in a crystal, it is not possible to determine potential-derived charges for atoms in a crystal. To overcome this limitation, we present a novel method for determining atomic charges for a molecule in a crystal based on a fit to the electric field at points on a surface around the molecule. Examples of fits to the electric field at points on a Hirshfeld surface, using crystal Hartree-Fock electron densities computed with a DZP basis set are presented for several organic molecular crystals. The field-derived charges for common functional groups are transferable, and reflect chemical functionality as well as the subtle effects of intermolecular interactions. The charges also yield an excellent approximation to the electric field surrounding a molecule in a crystal for use in cluster calculations on molecules in solids.     

Fluctuating charge normal modes: An algorithm for implementing molecular dynamics simulations with polarizable potentials

A new method for performing molecular dynamics simulations with fluctuating charge polarizable potentials is introduced. In fluctuating charge models, polarizability is treated by allowing the partial charges to be variables, with values that are coupled to charges on the same molecule as well as those on other molecules. The charges can be efficiently propagated in a molecular dynamics simulation using extended Lagrangian dynamics. By making a coordinate change from the charge variables to a set of normal mode charge coordinates for each molecule, a new method is constructed in which the normal mode charge variables uncouple from those on the same molecule. The method is applied to the TIP4P-FQ model of water and compared to other methods for implementing the dynamics. The methods are compared using different molecular dynamics time steps.     

基于分子参数的药物小肠吸收预测模型

选择100个化合物作为数据集,随机选取其中80个为训练集,其他分子为验证集,并为每个化合物分子计算了30个参数.通过采用五种不同多元线性回归分析方法对其训练模拟,建立了数学模型,并用验证集检验了所建模型的预测能力.结果发现向后筛选法为最优小肠吸收建模方法.由该法所建模型的统计结果良好(R2>0.80),应用于验证集时也表现出较强预测能力.该模型确定了对小肠吸收影响较大的分子参数,有助于指导进一步的新药筛选和开发.     

Effect of the Solute Cavity on the Solvation Energy and its Derivatives within the Framework of the Gaussian Charge Scheme

The treatment of the solvation charges using Gaussian functions in the polarizable continuum model results in a smooth potential energy surface. These charges are placed on top of the surface of the solute cavity. In this article, we study the effect of the solute cavity (van der Waals-type or solvent-excluded surface-type) using the Gaussian charge scheme within the framework of the conductor-like polarizable continuum model on (a) the accuracy and computational cost of the self-consistent field (SCF) energy and its gradient and on (b) the calculation of free energies of solvation. For that purpose, we have considered a large set of systems ranging from few atoms to more than 200 atoms in different solvents. Our results at the DFT level using the B3LYP functional and the def2-TZVP basis set show that the choice of the solute cavity does neither affect the accuracy nor the cost of calculations for small systems (< 100 atoms). For larger systems, the use of a vdW-type cavity is recommended, as it prevents small oscillations in the gradient (present when using a SES-type cavity), which affect the convergence of the SCF energy gradient. Regarding the free energies of solvation, we consider a solvent-dependent probe sphere to construct the solvent-accessible surface area required to calculate the nonelectrostatic contribution to the free energy of solvation. For this part, our results for a large set of organic molecules in different solvents agree with available experimental data with an accuracy lower than 1 kcal/mol for both polar and nonpolar solvents.     

Advances in electric field and atomic surface derived properties from experimental electron densities

The present study is devoted to a general use of the Gauss law. This is applied to the atomic surfaces derived from the topological analysis of the electron density. The method proposed here is entirely numerical, robust and does not necessitate any specific parametrization of the atomic surfaces. We focus on two fundamental properties: the atomic charges and the electrostatic forces acting on atoms in molecules. Application is made on experimental electron densities modelized by the Hansen-Coppens model from which the electric field is derived for a heterogenic set of compounds: water molecule, NO(3) anion, bis-triazine molecule and MgO cluster. Charges and electrostatic forces are estimated by the atomic surface flux of the electric field and the Maxwell stress tensor, respectively. The charges obtained from the present method are in good agreement with those issued from the conventional volume integration. Both Feynman and Ehrenfest forces as well as the electrostatic potential at the nuclei (EPN) are here estimated from the experimental electron densities. The values found for the molecular compounds are presented and discussed in the scope of the mechanics of atomic interactions.     

Spectroscopic consequences of a mixed valence excited state: quantitative treatment of a dihydrazine diradical dication

A model for the quantitative treatment of molecular systems possessing mixed valence excited states is introduced and used to explain observed spectroscopic consequences. The specific example studied in this paper is 1,4-bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)-2,3,5,6-tetramethylbenzene-1,4-diyl dication. The lowest energy excited state of this molecule arises from a transition from the ground state where one positive charge is associated with each of the hydrazine units, to an excited state where both charges are associated with one of the hydrazine units, that is, a Hy-to-Hy charge transfer. The resulting excited state is a Class II mixed valence molecule. The electronic emission and absorption spectra, and resonance Raman spectra, of this molecule are reported. The lowest energy absorption band is asymmetric with a weak low-energy shoulder and an intense higher energy peak. Emission is observed at low temperature. The details of the absorption and emission spectra are calculated for the coupled surfaces by using the time-dependent theory of spectroscopy. The calculations are carried out in the diabatic basis, but the nuclear kinetic energy is explicitly included and the calculations are exact quantum calculations of the model Hamiltonian. Because the transition involves the transfer of an electron from the hydrazine on one side of the molecule to the hydrazine on the other side and vice versa, the two transitions are antiparallel and the transition dipole moments have opposite signs. Upon transformation to the adiabatic basis, the dipole moment for the transition to the highest energy adiabatic surface is nonzero, but that for the transition to the lowest surface changes sign at the origin. The energy separation between the two components of the absorption spectrum is twice the coupling between the diabatic basis states. The bandwidths of the electronic spectra are caused by progressions in totally symmetric modes as well as progressions in the modes along the coupled coordinate. The totally symmetric modes are modeled as displaced harmonic oscillators; the frequencies and displacements are determined from resonance Raman spectra. The absorption, emission, and Raman spectra are fit simultaneously with one parameter set. The coupling in the excited electronic state H(ab)(ex) is 2000 cm(-1). Excited-state mixed valence is expected to be an important contributor to the electronic spectra of many organic and inorganic compounds. The energy separations and relative intensities enable the excited-state properties to be calculated as shown in this paper, and the spectra provide new information for probing and understanding coupling in mixed valence systems.     

Antagonistic properties of a natural product-Bicuculline with the gamma-aminobutyric acid receptor: studied through electrostatic potential mapping, electronic and vibrational spectra using ab initio and density functional theory

(+)-Bicuculline (hereinafter referred to as bicuculline), a phthalide isoquinoline alkaloid is of current interest as an antagonist of gamma-aminobutyric acid (GABA). Its inhibitor properties have been studied through molecular electrostatic potential (MEP) mapping of this molecule and GABA receptor. The hot site on the potential surface of bicuculline, which is also isosteric with GABA receptor, has been used to interpret the inhibitor property. A systematic quantum chemical study of the possible conformations, their relative stabilities, FT-Raman, FT-IR and UV-vis spectroscopic analysis of bicuculline has been reported. The optimized geometries, wavenumber and intensity of the vibrational bands of all the conformers of bicuculline have been calculated using ab initio Hartree-Fock (HF) and density functional theory (DFT) employing B3LYP functional and 6-311G(d,p) basis set. Mulliken atomic charges, HOMO-LUMO gap ΔE, ionization potential, dipole moments and total energy have also been obtained for the optimized geometries of both the molecules. TD-DFT method is used to calculate the electronic absorption parameters in gas phase as well as in solvent environment using integral equation formalism-polarizable continuum model (IEF-PCM) employing 6-31G basis set and the results thus obtained are compared with the UV absorption spectra. The combination of experimental and calculated results provides an insight into the structural and vibrational spectroscopic properties of bicuculline.     

Fast,efficient generation of high‐quality atomic charges. AM1‐BCC model: I. Method

The AM1‐BCC method quickly and efficiently generates high‐quality atomic charges for use in condensed‐phase simulations. The underlying features of the electron distribution including formal charge and delocalization are first captured by AM1 atomic charges for the individual molecule. Bond charge corrections (BCCs), which have been parameterized against the HF/6‐31G* electrostatic potential (ESP) of a training set of compounds containing relevant functional groups, are then added using a formalism identical to the consensus BCI (bond charge increment) approach. As a proof of the concept, we fit BCCs simultaneously to 45 compounds including O‐, N‐, and S‐containing functionalities, aromatics, and heteroaromatics, using only 41 BCC parameters. AM1‐BCC yields charge sets of comparable quality to HF/6‐31G* ESP‐derived charges in a fraction of the time while reducing instabilities in the atomic charges compared to direct ESP‐fit methods. We then apply the BCC parameters to a small “test set” consisting of aspirin, d ‐glucose, and eryodictyol; the AM1‐BCC model again provides atomic charges of quality comparable with HF/6‐31G* RESP charges, as judged by an increase of only 0.01 to 0.02 atomic units in the root‐mean‐square (RMS) error in ESP. Based on these encouraging results, we intend to parameterize the AM1‐BCC model to provide a consistent charge model for any organic or biological molecule. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 132–146, 2000     

Effect of charge distribution on electrostatic chromophore—protein interactions in Bacteriorhodopsin

Charge distributions of a protonated and unprotonated Schiff base model compound are determined using different quantum chemical methods. After fitting the model molecule onto the protonated retinal Schiff base in Bacteriorhodopsin, electrostatic interaction energies between the model molecule and protein are calculated. Interaction energies as well as the calculated pK_1/2 values of the model molecule are shown to depend considerably on the chosen charge distribution. Electrostatic potential derived partial charges determined at different ab initio levels reveal interaction energies between the model molecule and nearby residues such as ARG-82, ASP-85, and ASP-212, which are relatively method independent. Consequently, such charge distributions also result in pK_1/2 values for the model molecule that are very similar. Larger deviations in the electrostatic interaction energies, however, are found in the case of charge distributions derived according to the Mulliken population analysis. Nevertheless, some sets of Mulliken derived partial charges predicted pK_1/2 values for the model molecule that are close to those determined with electrostatic potential derived partial charges. This agreement, however, is only achieved because the individual errors of the contributing terms are approximately compensated. The use of the extended atom model is shown to be problematic. Although potential derived charges can correctly describe electrostatic interaction energies, they fail to predict pK_1/2 values. On the basis of the present investigation a new set of partial charges for the protonated and unprotonated retinal Schiff base is proposed to be used in molecular dynamics simulations and electrostatics calculations. © 1997 by John Wiley & Sons, Inc.     

pH and Charge Effects Behind the Interaction of Artepillin C,the Major Component of Green Propolis,With Amphiphilic Aggregates: Optical Absorption and Fluorescence Spectroscopy Studies

Brazilian green propolis is one of the bee products most consumed in the world to prevent diseases, owing antioxidant, antimicrobial, anti‐inflammatory and antitumor activities. The major component of Brazilian green propolis is Artepillin C (ArtC), a cinnamic acid derivative with two prenylated groups that improve the affinity of the compound for lipophilic environment. Here, we have employed optical absorption and fluorescence techniques to draw conclusions on how ArtC interacts with amphiphilic aggregates commonly used as model membranes having different charges in the polar head group. Optical absorption spectra were representative of the protonation state of ArtC, dictated by the local pH at the surface of micelles and lipid vesicles. Fluorescence results showed that, in the presence of micelles and vesicles, the polarizability around ArtC was modified, compared to the value in aqueous medium, and the molecule should be located preferentially on the surface region of the model membranes, with an enhanced interaction with the less ordered state of the lipid vesicles.     

Charges fit to electrostatic potentials. II. Can atomic charges be unambiguously fit to electrostatic potentials?

The present work examines the conditioning of the least-squares matrix for obtaining potential derived charges and presents a modification of the CHELP method for fitting atomic charges to electrostatic potentials. Results from singular value decompositions (SVDs) of the least-squares matrices show that, in general, the least-squares matrix for this fitting problem will be rank deficient. Thus, statistically valid charges cannot be assigned to all the atoms in a given molecule. We find also that, contrary to popular notions, increasing the point density of the fit has little or no influence on the rank of the problem. Improvement in the rank can best be achieved by selecting points closer to the molecular surface. Basis set has, as expected, no effect on the number of charges that can be assigned. Finally, a well-defined, computationally efficient algorithm (CHELP-SVD) is presented for determining the rank of the least-squares matrix in potential-derived charge fitting schemes, selecting the appropriate subset of atoms to which charges can be assigned based on that rank estimate, and then refitting the selected set of charges. © 1996 by John Wiley & Sons, Inc.     

ClogPalk: a method for predicting alkane/water partition coefficient

Alkane/water partition coefficients (P_alk) are less familiar to the molecular design community than their 1-octanol/water equivalents and access to both data and prediction tools is much more limited. A method for predicting alkane/water partition coefficient from molecular structure is introduced. The basis for the ClogP_alk model is the strong (R² = 0.987) relationship between alkane/water partition coefficient and molecular surface area (MSA) that was observed for saturated hydrocarbons. The model treats a molecule as a perturbation of a saturated hydrocarbon molecule with the same MSA and uses increments defined for functional groups to quantify the extent to which logP_alk is perturbed by the introduction each functional group. Interactions between functional groups, such as intramolecular hydrogen bonds are also parameterized within a perturbation framework. The functional groups and interactions between them are specified substructurally in a transparent and reproducible manner using SMARTS notation. The ClogP_alk model was parameterized using data measured for structurally prototypical compounds that dominate the literature on alkane/water partition coefficients and then validated using an external test set of 100 alkane/water logP measurements, the majority of which were for drugs.     

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.     

周期性密度泛函理论研究氯气在CuCl(111)表面上的吸附与解离

运用广义梯度密度泛函理论(Generalized Gradient Approximation，GGA)的PBE(Perdew-Burke-Ernzerh)方法结合周期性平板模型，研究了氯气分子和氯原子在CuCl(111)表面上的吸附。通过对不同吸附位和不同单层覆盖度下的吸附能和几何构型参数的计算和比较发现：氯气分子在CuCl(111)表面的吸附为解离吸附；单层覆盖度为0.50时的吸附构型为稳定的吸附构型；氯气分子平行吸附在CuCl(111)表面时最稳定，吸附能最大，达364.5 kJ·mol^-1；伸缩振动频率的计算结果表明，吸附后的氯气分子的伸缩振动频率与自由氯气分子的伸缩振动频率相比，都发生了红移；布居分析结果表明整个吸附体系发生了由Cu原子向氯气分子的电荷转移。氯原子吸附的计算结果显示氯原子以穴位稳定的吸附在CuCl(111)表面。