Papers by James Rabinowitz
How do computational molecular modeling methods enable the incorporation of structural and mechan... more How do computational molecular modeling methods enable the incorporation of structural and mechanistic information into the extrapolations necessary for determining the potential risks of chemicals in the environment? A. Determining bioassay priorities B. Molecular level detail of mechanisms of action
Which chemicals are most likely to bind to steroid hormone receptors and disrupt the endocrine sy... more Which chemicals are most likely to bind to steroid hormone receptors and disrupt the endocrine system? Research Goals • Utilize quantum chemistry and other molecular modeling methods in order to develop computational predictive tools that can be used to screen for endocrine disrupting effects. • Interface the virtual screening tools with complementary experimental and computational approaches such as the ToxCast initiative in order to aid the Agency in prioritizing data requirements for risk assessment. ToxCast is a multi-level information domain scheme for studying chemical toxicity, an NCCT initiative led by Robert Kavlock, David Dix, and Keith Houck. – First phase: Perform a comprehensive study on a set of diverse chemicals across all information domains. – Second phase: The information that is gathered will be used to extract relationships among the information domains. – Third phase: Utilize these relationships to inform computer models in order to improve their abilities to su...
Science Question Pyrethroids are a chemical class of widely used insecticides, and at least 16 ch... more Science Question Pyrethroids are a chemical class of widely used insecticides, and at least 16 chemicals in this class are registered for use in the U.S. Their mode of action in insects is to disrupt the sodium ion channels in nerve cell membranes and thus alter the normal function of the nervous system. These channels are also important target sites in mammals, but information on the effects of this class of chemicals on humans is limited. Experimental measurements of the hydrolysis of pyrethroids indicate differential rates of metabolism based on stereochemistry. How do physical and chemical structure determine the role of pyrethroids in mechanisms of toxicity? Physiologically-based pharmacokinetic (PBPK) models of the chemical toxicity of pyrethroids are being developed by scientists in ORD/NERL. However, a limitation of PBPK models is the difficulty in obtaining experimentally-measured values for some parameters, especially for human models. Estimates for some parameters can be ...
1973 IEEE G-MTT International Microwave Symposium, 1973
Theoretical analysis of the possible modes of molecular interaction with microwave radiation sugg... more Theoretical analysis of the possible modes of molecular interaction with microwave radiation suggests that the absorption of a microwave photon may interfere with stereospecific bimolecular processes.
Mutation Research/Reviews in Genetic Toxicology, 1989
Mutation Research/Genetic Toxicology, 1988
Computer-generated genetic activity profiles and pairwise matching procedures may aid in the sele... more Computer-generated genetic activity profiles and pairwise matching procedures may aid in the selection of the most appropriate short-term bioassays to be used in test batteries for the evaluation of the genotoxicity of a given chemical or group of chemicals. Selection of test batteries would be based on a quantitative comparative assessment of the past performance of similar tests applied to other chemicals of the same structural group. The information potentially available for test-battery selection through the use of this pattern-recognition technique is considerably greater than the qualitative results obtained from individual short-term tests. Application of the method should further our understanding of the relationships between chemical properties and genotoxic responses obtained in short-term bioassays and also may contribute to our knowledge of the mechanisms of complex processes such as carcinogenesis. This approach to battery selection should be augmented by careful consideration of established principles of genetic toxicity testing; that is, a chemical should be evaluated in a battery of tests representing the full range of relevant genetic endpoints.
Xenobiotica, 1991
1. The direction of epoxide ring opening may be predicted using the techniques of theoretical che... more 1. The direction of epoxide ring opening may be predicted using the techniques of theoretical chemistry by comparing the computed total energy of the two possible carbocations formed. 2. To predict the direction of epoxide ring opening and the potential binding of aceanthrylene 1,2-epoxide to biopolymers, quantum mechanical calculations were performed on the two potential hydroxy carbocations. 3. The 2-hydroxy carbocation (II) was favoured over the 1-hydroxy carbocation by 11.8 kcal/mol. Molecule II had more positive charge at the meso carbon group than at the nominally charged 1 position. Both the lowest unoccupied molecular orbital and the molecular electrostatic potential confirm this result, and indicate the possibility of unusual adducts to biopolymers. 4. Similar calculations on the equivalent epoxides of acenaphthylene and acephenanthrylene do not show the same results. 5. Modelling the addition products of II with small nucleophiles indicates that these unusual addition products do not form, and that the interaction is controlled by electronic effects and not electrostatic effects. 6. The calculations on acephenanthrylene demonstrate the importance of including the hydroxyl group when making predictions relative to epoxide ring opening. 7. Molecular descriptors are surrogates for the interaction of that molecule with an often unknown biological target. In cases where molecular descriptors are used without information about the target, small quantitative differences may not be appropriate discriminators.
Polycyclic Aromatic Compounds, 1996
ABSTRACT We have investigated the induction of DNA adducts and adenomas in the lungs of strain A/... more ABSTRACT We have investigated the induction of DNA adducts and adenomas in the lungs of strain A/J mice following the i.p. administration of several polycyclic aromatic hydrocarbons (PAH): pyrene, dibenz[a,h]anthracene (DBA), benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), 5-methylchrysene (5-MeC), 3-methylcholanthrene (3-MC), and cyclopenta[cd]pyrene (CPP). All of the PAH induced lung adenomas, with relative tumor potency rankings as a function of administered dose: DBA = 3-MC > 5-MeC > CPP > B[a]P > B[b]F. DNA adducts reached maximal levels between 3 and 7 days after injection, followed by a gradual decrease. The time-integrated DNA adduct level (TIDAL) was calculated by numerically integrating the areas under the adduct persistence curves extrapolated out to 240 days for each PAH at each dose level. Tumorigenic potencies as a function of TIDAL values for 5-MeC, B[a]P, B[b]F, and CPP were all equal, while 3-MC was 2.6-fold more potent and DBA was 25.8-fold more potent.
Polycyclic Aromatic Compounds, 1996
Abstract Polycyclic aromatic hydrocarbons with a crowded bay region, like benzo[c]phenanthrene, a... more Abstract Polycyclic aromatic hydrocarbons with a crowded bay region, like benzo[c]phenanthrene, are nonplanar molecules with two helical structures. The bay region diol-epoxides of these PAHs retain the helical structure and therefore have twice as many possible conformations as the diol-epoxides of planar PAHs. Using quantum mechanical methods, it is shown that the conformation where the epoxide oxygen is near the distal ring is more stable than the conformation where it is away. The most stable syn- and anti- diastereomers for the diol-epoxides of five PAHs are computed. Computation of the electrostatic interaction between the epoxide group and the distal ring suggests that it provides the additional stabilization. Comparison is made between planar and nonplanar PAHs and between molecules where the crowding is due to a ring CH or a methyl group. These results suggest that the molecular electrostatic potential in the bay region can effect molecular reactivity.
Journal of Theoretical Biology, 1982
Journal of the American Chemical Society, 1993
The molecular mechanisms for nucleophilic addition of an ammonia molecule to three small molecule... more The molecular mechanisms for nucleophilic addition of an ammonia molecule to three small molecules with activated double bonds-acrolein (ACR), acrylonitrile (ACN), and acrylic acid (AA)-have been examined with ab initio quantum chemical methods in reactions modeling their interactions with biological targets. The calculations include the nucleophilic addition reaction of either an ammonia molecule or an NH3 hydrogen bonded to a discrete water molecule (NHyOH2) to ACR, ACN, and AA. Optimizations of the geometries of reactants and transition structures for the 1,2-and 1,Caddition mechanisms were done at the restricted Hartree-Fock level with 6-31G basis sets, and electron correlation energy was calculated at the MP2 level with 6-31G* basis sets. Reaction energies were corrected for zero-point energies calculated from the harmonic vibrational frequencies of the 6-3 1 G optimized structures. Hydration enthalpies were evaluated with the solvent described as a polarizable dielectric continuum. The barriers calculated for the addition reactions were found to be significantly reduced by the assistance of a solvent molecule in the intramolecular proton-transfer process. The order of reactivities, based on energies of activation of the 1 ,Caddition to ACR, either 1,2-or 1,4-addition to AA, and 1,2-addition to ACN, is as follows: ACR > AA > ACN, in very good agreement with experimental results. The results provide inferences regarding the relative capabilities of the molecules in this class to interact with DNA and reflect on their relative potencies in reactions determining the biological effects of these environmentally important chemical species.
Journal of the American Chemical Society, 1988
The reactivities of derivatives of acrylic acid in nucleophilic Michael addition are evaluated fr... more The reactivities of derivatives of acrylic acid in nucleophilic Michael addition are evaluated from a study of the mechanism of addition of a nucleophile, F, to the activated double bond of acrylic acid (AA) and methacrylic acid (MAA).
Journal of Computational Chemistry, 1990
The electrostatic potential V(r) that the nuclei and electrons of a molecule create in the surrou... more The electrostatic potential V(r) that the nuclei and electrons of a molecule create in the surrounding space is well established as a guide in the study of molecular reactivity, and particularly, of biological recognition processes. Its rigorous computation is, however, very demanding of computer time for large molecules, such as those of interest in recognition interactions. We have accordingly investigated the use of an approximate finite multicenter multipole expansion technique to determine its applicability for producing reliable electrostatic potentials of dibenzo‐p‐dioxins and related molecules, with significantly reduced amounts of computer time, at distances of interest in recognition studies. A comparative analysis of the potentials of three dibenzo‐p‐dioxins and a substituted naphthalene molecule computed using both the multipole expansion technique and Gaussian 82 at the STO‐5G level has been carried out. Overall we find that regions of negative and positive V(r) at 1.75...
Journal of Computational Chemistry, 1998
Interaction with the ligand binding domain of receptors for natural chemicals present one potenti... more Interaction with the ligand binding domain of receptors for natural chemicals present one potential mechanism for the biological effects of environmental chemicals. Evidence suggests that the electrostatic interaction between the ligand and the receptor is an important component for binding to some of the relevant receptors. The presence of charged residues near the binding site suggests that the charge distribution of the free ligand may be different from the charge distribution of the ligand as it approaches the binding domain of the protein. In this study a new type of potential is computed for a series of dibenzo‐p‐dioxin (dioxin) ligands. This quantum mechanically computed potential results from interaction between the ligand and a trimethyl ammonium probe at a set of grid points. This interaction potential is compared with the molecular electrostatic potential computed from the wave function of the isolated ligands. Three types of local minima are found: (1) above the oxygen; (2) above the conjugated ring; and (3) above the chlorine(s). The molecular electrostatic potential emphasizes the minima associated with the chlorine atoms and, in that potential, the minima associated with the oxygen atoms disappear with chlorination. In the new potential, the minima over the oxygen atoms are maintained even in tetrachlorodioxin. As chlorination is increased the differences between the two potentials increases. The new potential shows the influence of the π‐cation interaction, which is largest when there is little substitution on the ring. The presence of the probe induces a dipole component of 1 debye perpendicular to the plane of the ligand. Local minima in the interaction potential are then used as starting structures for the determination of the most stable ligand–probe complexes. The most stable structures are obtained from the minima associated with the oxygen atoms. These structures are stabilized by a hydrogen bond formation between the probe and the oxygen and the molecule is bent by 30° about the O(SINGLE BOND)O axis. For this series of molecules, the new potential retains some of the features that determine the hydrogen bond whereas the molecular electrostatic potential does not. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 673–684, 1998
International Journal of Quantum Chemistry, 1994
In computational studies to understand the interaction of polycyclic aromatic hydrocarbons (PAHs)... more In computational studies to understand the interaction of polycyclic aromatic hydrocarbons (PAHs) with biomolecular systems, the semiempirical method AM1 has been used previously to determine the geometry of the PAH and its metabolites and relevant intermediates. A number of studies have shown that AM1 provides geometries for parent PAHs that are acceptably close to experimentally determined structures. However, many of the properties that determine the manner by which PAHs interact with biological nucleophiles depend on the structure of metabolites and reactive intermediates where less experimental information is available. In a previous study, we used AM1 to obtain the molecular geometries of reactive intermediates of cyclopenta‐PAHs (cPAHs) and then used single‐point Hartree‐Fock calculations, with the gaussian 3‐21g basis set, to obtain molecular energies and charge distributions, in order to predict the direction of epoxide ring opening. Recent advances in the availability of c...
International Journal of Quantum Chemistry, 1988
Two molecular charge similarity index (CSI) methods are further evaluated for practical applicati... more Two molecular charge similarity index (CSI) methods are further evaluated for practical application: one method based on a simple CNDO‐type approximation to the electron density function and the other based on an ab initio pseudo total charge density function. The test system consists of isosteric analogues of dimethyl ether and methoxy acetic acid. The effects of differences in skeletal structure on the CSI measure of electron density similarity about corresponding atoms is estimated, and two new developments are presented for application of the ab initio‐based method: (1) an INDO‐type approximation which improves the efficiency of the CSI calculation; and (2) a FOCUS feature which enables comparisons of local molecule regions.
International Journal of Quantum Chemistry, 1988
The electrostatic interaction is a critical component of intermolecular interactions in biologica... more The electrostatic interaction is a critical component of intermolecular interactions in biological processes. Rapid methods for the computation and characterization of the molecular electrostatic potential (MEP) that segment the molecular charge distribution and replace this continuous function by a series of multipole moments for each segment have been described. There are two sources of error in these techniques: 1( The truncation of the expansion after just a few terms, and 2) the charge in the segmental distribution that is more distant from the expansion center than the observation point. The first may be eliminated by finite expansion methods where truncation is unnecessary or performed in a manner that gives errors that are acceptably small. The second is inherent in the multipole expansion and results from the assumption in performing the expansion that the distance to the observation point is larger than the distance to all points inside the charge distribution. As the basis functions used in molecular wave functions have infinite extent, this will never be the case and the multipole expansion is never strictly valid. In practice this inherent error limits the range of usefulness of all multipole expansion techniques. To expand this range we have introduced a method that uses exact techniques to compute the MEP for the part of the molecular charge distribution described by the gaussians on each atom with the smallest exponential parameter and uses segmental multipole methods for the remainder of the charge. Using pyrrole with an STO-3G wave function as an example, this method significantly improves the potential in the range 1.4–2.0 A from atoms with only a small increase in computational effort. If other basis sets are used with more diffuse gaussians the convergence of the multipole expansion will be at greater distances from the atoms and this type of correction will be more important.
International Journal of Quantum Chemistry, 2009
IEEE Transactions on Microwave Theory and Techniques, 1973
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Papers by James Rabinowitz