Aneta Jezierska

Car-Parrinello simulation of an O–H stretching envelope and potential of mean force of an intramolecular hydrogen bonded system: Application to a Mannich base in solid state and in vacuum

Car-Parrinello molecular dynamics (CPMD) study was performed for an anharmonic system-an intramolecularly hydrogen bonded Mannich-base-type compound, 4,5-dimethyl-2(N,N-dimethylaminemethyl)phenol, to investigate the vibrational spectrum associated with the O-H stretching. Calculations were carried out for the solid state and for an isolated molecule. The classical CPMD simulation was performed and then the proton potential snapshots were extracted from the trajectory. The vibrational Schrodinger equation for the snapshots was solved numerically, and the (O-H) envelope was calculated as a superposition of the 0-->1 transitions. The potential of mean force for the proton stretching mode was calculated from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling, nuclear quantum effects, and effects of the environment. Perspectives for application of the presented methodology in the computational support of biocatalysis are given in the study.

Modeling toxicity by using supervised kohonen neural networks.

Counterprogation neural network is shown to be a powerful and suitable tool for the investigation of toxicity. This study mined a data set of 568 chemicals. Two hundred eighty-two objects were used as the training set and 286 as the test set. The final model developed presents high performances on the data set R(2) = 0.83 (R(2) = 0.97 on the training set, R(2) = 0.59 on the test set). This technique distinguishes itself also for the ability to give to the expert two-dimensional maps suitable for the study of the distribution/clustering of the data and the identification of outliers.

Quantitative and qualitative models for carcinogenicity prediction for non-congeneric chemicals using CP ANN method for regulatory uses

The new European chemicals regulation Registration, Evaluation, Authorization and Restriction of Chemicals entered into force in June 2007 and accelerated the development of quantitative structure–activity relationship (QSAR) models for a variety of endpoints, including carcinogenicity. Here, we would like to present quantitative (continuous) and qualitative (categorical) models for non-congeneric chemicals for prediction of carcinogenic potency. A dataset of 805 substances was obtained after a preliminary screening of findings of rodent carcinogenicity for 1,481 chemicals accessible via Distributed Structure-Searchable Toxicity (DSSTox) Public Database Network originated from the Lois Gold Carcinogenic Potency Database (CPDB). Twenty seven two-dimensional MDL descriptors were selected using Kohonen mapping and principal component analysis. The counter propagation artificial neural network (CP ANN) technique was applied. Quantitative models were developed exploring the relationship between the experimental and predicted carcinogenic potency expressed as a tumorgenic dose TD50 for rats. The obtained models showed low prediction power with correlation coefficient less than 0.5 for the test set. In the next step, qualitative models were developed. We found that the qualitative models exhibit good accuracy for the training set (92%). The model demonstrated good predicted performance for the test set. It was obtained accuracy (68%), sensitivity (73%), and specificity (63%). We believe that CP ANN method is a good in silico approach for modeling and predicting rodent carcinogenicity for non-congeneric chemicals and may find application for o ther toxicological endpoints.

On the Oligomeric State of DJ-1 Protein and Its Mutants Associated with Parkinson Disease A COMBINED COMPUTATIONAL AND IN VITRO STUDY

Mutations in the DJ-1 protein are present in patients suffering from familial Parkinson disease. Here we use computational methods and biological assays to investigate the relationship between DJ-1 missense mutations and the protein oligomeric state. Molecular dynamics calculations suggest that: (i) the structure of DJ-1 wild type (WT) in aqueous solution, in both oxidized and reduced forms, is similar to the crystal structure of the reduced form; (ii) the Parkinson disease-causing M26I variant is structurally similar to the WT, consistent with the experimental evidence showing the protein is a dimer as WT; (iii) R98Q is structurally similar to the WT, consistent with the fact that this is a physiological variant; and (iv) the L166P monomer rapidly evolves toward a conformation significantly different from WT, suggesting a change in its ability to oligomerize. Our combined computational and experimental approach is next used to identify a mutant (R28A) that, in contrast to L166P, destabilizes the dimer subunit-subunit interface without significantly changing secondary structure elements.

H-Bonded Complexes of Aniline with HF/F− and Anilide with HF in Terms of Symmetry-Adapted Perturbation, Atoms in Molecules, and Natural Bond Orbitals Theories

The hydrogen-bonded isoelectronic complexes of aniline with HF/F- and an ionic form of aniline with HF were investigated by use of computational methods: Symmetry-Adapted Perturbation Theory (SAPT), Atoms in Molecules (AIM), and Natural Bond Orbitals (NBO) approaches. All computations were based on structural models previously generated at the B3LYP/6-311+(d,p) level. The differences between neutral (Ph-NH2...HF)and anionic (Ph-NH2...F- and Ph-NH-...HF) complexes were clearly outlined. The discussed charged complexes serve as Lewis acids and base, HF and F-, respectively. It was found that electrostatic and induction energy terms, obtained as a result of the SAPT method, are most dependent on the type of H-bonding (i.e.,charged or neutral). The electrostatic term is the most distinctive between the neutral and charge-assisted hydrogen bonds in the investigated two-body systems, whereas the latter is more significant in the case of weaker interactions (larger H...B distances). Application of Principal Component Analysis (PCA) to energy components obtained from the SAPT procedure indicated that all of them are relatively well intercorrelated.The above-mentioned terms together with the exchange energy terms are the most important contributions ofthe main principal component, which describes 95% of the total variance. Comparison of AIM parameters in bond critical points for modeled H-bond systems shows a good agreement with those from equilibrium complexes, both experimental and calculated ones. It was found that charged H-bonded complexes exhibit larger fluctuation of electron density and its Laplacian in bond critical points, in line with SAPT analysis. NBO results confirmed the effect of the strength of interaction on property changes both in the region of H-bonding and outside of it. The latter, more distant consequences follow the Bent-Walsh rule for all studied complexes.

Structural and spectroscopic properties of an aliphatic boronic acid studied by combination of experimental and theoretical methods

Boronic acids have emerged as one of the most useful class of organoboron molecules, with application in synthesis, catalysis, analytical chemistry, supramolecular chemistry, biology, and medicine. In this study, the structural and spectroscopic properties of n-butylboronic acid were investigated using experimental and theoretical approaches. X-ray crystallography method provided structural information on the studied compound in the solid state. Infrared and Raman spectroscopy served as tools for the data collection on vibrational modes of the analyzed system. Car-Parrinello molecular dynamics simulations in solid state were carried out at 100 and 293 K to investigate an environmental and temperature influence on molecular properties of the n-butylboronic acid. Analysis of interatomic distances of atoms involved in the intermolecular hydrogen bond was performed to study the proton motion in the crystal. Subsequently, Fourier transform of autocorrelation functions of atomic velocities and dipole moment was applied to study the vibrational properties of the compound. In addition, the inclusion of quantum nature of proton motion was performed for O-H stretching vibrational mode by application of the envelope method for intermolecular hydrogen-bonded system. The second part of the computational study consists of simulations performed in vacuo. Monomeric and dimeric forms of the n-butylboronic acid were investigated using density functional theory and Moller-Plesset second-order perturbation method. The basis set superposition error was estimated. Finally, atoms in molecules (AIM) theory was applied to study electron density topology and properties of the intermolecular hydrogen bond. Successful reproduction of the molecular properties of the n-butylboronic acid by computational methodologies, presented in the manuscript, indicates the way for future studies of large boron-containing organic systems of importance in biology or materials science.

First-Principle Molecular Dynamics Study of Selected Schiff and Mannich Bases: Application of Two-Dimensional Potential of Mean Force to Systems with Strong Intramolecular Hydrogen Bonds.

Car-Parrinello Molecular Dynamics simulations were performed for selected anharmonic systems, i.e., Schiff and Mannich base-type compounds, to investigate the vibrational properties associated with O-H stretching. All calculations were performed in the gas phase to compare them with available experimental data. First the vibrational properties of the two compounds were analyzed on the basis of well-established approaches:  Fourier transformation of the autocorrelation function of both the atomic velocities and dipole moments. Then path integral molecular dynamics simulations were performed to demonstrate the influence of quantum effects on the protons position in the hydrogen bridge. In addition, quantum effects were incorporated a posteriori into calculations of O-H stretching envelopes for the Schiff and Mannich bases. Proton potential snapshots were extracted from the ab initio molecular dynamics trajectory. Vibrational Schrödinger equations (one- and two-dimensional) were solved numerically for the snapshots, and the O-H stretching envelopes were calculated as a superposition of the 0→1 transitions. Subsequently, one- and two-dimensional potentials of mean force (1D and 2D pmf) were calculated for the proton stretching mode from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling and nuclear quantum effects. The results show that the applied methodologies are in good agreement with experimental infrared spectra. Additionally, it is demonstrated that the 2D pmf method could be applied in systems with strong anharmonicity to describe the properties of the O-H stretching mode more accurately. Future applications of the 2D pmf technique include, in principle, large biomolecular systems treated within the QM/MM framework.

Spectroscopic Properties of a Strongly Anharmonic Mannich Base N-oxide

Car-Parrinello molecular dynamics simulations in vacuum and in the solid state are performed on a strongly anharmonic system, namely, 2-(N-diethylamino-N-oxymethyl)-4,6-dichlorophenol, to investigate its molecular and spectroscopic properties. The investigated compound contains two slightly different molecules in the crystal cell with very short intramolecular hydrogen bonds (of 2.400 and 2.423 A), as determined previously by neutron diffraction. The vibrational properties of the compound are studied on the basis of standard approaches, that is, Fourier transformation of the autocorrelation functions of the atomic velocities and dipole moments. Then, the trajectory obtained from ab initio molecular dynamics is sampled and the obtained snapshots are used to solve the vibrational Schrödinger equations and to calculate the O--H stretching envelope as a superposition of the 0-->1 transition. Using an envelope method, the a posteriori quantum effects are included in the O--H stretching. In addition, NMR spectra are calculated also using the obtained snapshots. One- and two-dimensional potentials of mean force (1D and 2D pmf) are derived to explain the details of the proton dynamics. The computational results are supported by NMR experimental data. In addition, the calculated results are compared with previously published X-ray, neutron diffraction, and spectroscopic descriptions. A detailed analysis of the bridged protons dynamics is thus obtained. The application of 1D and 2D pmf in a system with a strong bridged-proton delocalization is also demonstrated.

Molecular modeling study of leflunomide and its active metabolite analogues.

Leflunomide is known as a compound with various sorts of biological activity, which found a practical application in medicine. Search of current literature revealed an active metabolite of Leflunomide together with its eight analogues synthesized as protein tyrosine kinase inhibitors with potential anticancer activity. Accurate description of the molecular structure of these compounds is valuable. The detailed geometrical parameters description was performed using DFT theory. The conformational analysis and intramolecular proton transfer were considered. Using the most stable conformation the detailed electronic structure description was obtained by analysis of electron density and electrostatic potential distribution in the first step. Next, the topological analysis of the electron density by AIM method and electron localization function (ELF) theories supplemented this study. The AIM and ELF theories were applied to study the topology of the molecules, atomic charges distribution, and details of bonding. The theoretical investigations were performed in the gas phase and by using SCRF/PCM solvent reaction field. In this study the molecular modeling results for Leflunomide and the analogues of its active metabolite are presented.

Counter-propagation artificial neural network as a tool for the independent variable selection: Structure-mutagenicity study on aromatic amines

The counter-propagation artificial neural network (CP ANN) technique was applied for the independent variable selection and for structure-mutagenic potency modeling on a set of 95 aromatic and heteroaromatic amines with biological activity investigated experimentally by an in vitro assay. The molecular structures were represented by 275 independent variables classified as topostructural, topochemical, geometrical and quantum-chemical descriptors. As a result of the neural network modeling, the following descriptors were found to be the most important for structure-activity relationship:5χ -path connectivity index of order h= 5, 3χbC-bond cluster connectivity index of order h= 3, JB-Balabans J index based on bond types, SHSNH2-electrotopological state index values for atoms, phia-flexibility index (κp1 ×κp2/nvx), IC0-mean information content or complexity of a graph based on the 0 order neighborhood of vertices in a hydrogen-filled graph and ELUMO. The leave one out (LOO) method was used in order to test and select the models for mutagenicity prediction. The statistical parameters for the 7-descriptors model are RModel= 0.96 and Rcv= 0.85, respectively. In the next step, the number of variables was reduced and the 4-descriptors model was found (RModel= 0.95 and Rcv= 0.85) and classified as the best one.