Complete model for the statistical composition of the end-plate potential.
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Computers↗
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Results for “quantum computing”
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QM/MM study of D-fructose in aqueous solution.
The QM/MM molecular dynamics methodology was applied to the study of the two main D-fructose tautomers present in aqueous solution, beta-D-fructofuranose and beta-D-fructopyranose. The solute was treated at the AM1 semi-empirical level, and for the solvent water molecules we used the TIP3P potential. We analyzed the structure of the water molecules around the hydroxyl groups to explain the differences in sweet taste between the two tautomers.
Carbohydrate Conformation↗
Isolating quantum coherences in structural imaging using intermolecular double-quantum coherence MRI.
Intermolecular multiple-quantum coherence (iMQC) MR imaging provides a fundamentally different contrast mechanism. It allows probing tissue microstructure by tuning the direction and strength of the correlation gradient. However, iMQC images of a specific quantum-coherence can easily be contaminated by leakage signals from undesired quantum coherences (zero, single, and triple quantum coherence in this work). Using a modified double-quantum CRAZED imaging sequence, we show that signals originating from various coherence orders (M=0, 1, 2, 3) can be predicted in k-space and effectively isolated by means of a four-step phase cycling scheme and judicious choice of flip angles. Finally, preliminary data suggest the method to be able to provide information on trabecular bone architecture such as regional mean trabecular plate separation.
Algorithms↗
Assigning vibrational polyads using relative equilibria: application to ozone.
We demonstrate how relative equilibria of a vibrating molecule, which are families of principal periodic orbits otherwise known as nonlinear normal modes, can be used to describe the global polyad structure of vibrational energy levels. The classical action integral n(E) computed along these orbits at different energies E corresponds to the polyad quantum number n so that the energy En of different relative equilibria describes the splitting of n-polyads. Further information on the internal polyad structure can be driven from the stability analysis of relative equilibria. We use the ozone molecule as a concrete example where n-polyads or "hyperpolyads" should be distinguished from the well-known polyads of the 1:1 stretching mode resonance; the stretching polyads are structural elements of hyperpolyads. We give dynamical interpretation of the relation between relative equilibria and n-polyads based on the normal form reduction in the limit of small vibrations near the equilibrium.
Models, Chemical↗
Molecular orbital calculations on the conformation of polypeptides and proteins. I. Preliminary investigations and simple dipeptides.
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Amides↗
Prediction of the genotoxicity of aromatic and heteroaromatic amines using electrotopological state indices.
In the past decade, electrotopological state (E-state) indices have come into their own as useful descriptors for correlating a variety of physicochemical and biological properties of chemical compounds. Genotoxicity and mutagenicity, however, appear not to have been previously considered. In the present study, the genotoxicity of a set of 95 aromatic and heteroaromatic amines, which has been modeled previously using several sets of parameters, is modeled using E-state indices, both with and without principal components analysis. Parallels are drawn between E-state indices that were important in these models and other types of descriptors found significant in previous studies, thus, shedding light on connections to the molecular mechanism of activity. The best result had a correlation coefficient r = 0.876 and a standard error s< or = 1 log unit. These values are comparable to those in previously published models that were based on topological/geometric or on physicochemical parameters. They are not as good as those for a model based on descriptors derived from extensive quantum mechanical analysis, but E-state indices are much easier to compute.
Amines↗
In silico prediction of medium effects on esterification equilibrium using the COSMO-RS method.
This paper presents a new approach for predicting solvent effects on esterification reactions of industrial importance in the field of biocatalysis. The COSMO-RS method has been used to calculate the activity coefficients of the chemical species involved in various reactions, carried out in different solvents. For comparison we also used the traditional UNIFAC method. Three lipase-catalyzed esterifications were considered: (1) 1-dodecanoic acid with menthol in n-hexane, n-heptane, cyclohexane, 2,2,4-trimethylpentane, toluene, acetonitrile, and 2-methyl-2-butanol; (2) 1-dodecanoic acid and 1-dodecanol in n-hexane, n-heptane, cyclohexane, 2,2,4-trimethylpentane, and toluene; and (3) glycerol and n-octanoic acid in acetonitrile, benzene, and toluene and in the neat reaction mixture (without any solvent). Predicted activities were used to calculate the thermodynamic equilibrium ratio. This should be independent of medium, and the variation in COSMO-RS values is at most 9-fold (corresponding to a DeltaG degrees of about 5.5 kJ/mol, which would still be a very useful prediction) and often only 2-fold (corresponding to less than 2 kJ/mol or 0.5 kcal/mol, therefore comparable with experimental error). UNIFAC is weaker, especially when important roles are played by conformational freedom, intramolecular interactions, strong polar effects, and charge distribution of molecules in the mixture. The relative percent deviations from the mean of equilibrium constants in different solvents range between 17 and 49 for COSMO-RS versus 32 to 65 for UNIFAC. The COSMO-RS method opens up new perspectives for the development of theoretical models for solvent selection with general applicability.
Catalysis↗
Solvation and structure of LiAlH(4) in ethereal solvents.
The nature of the solute species present in ethereal solutions of LiAlH(4) is of crucial importance for understanding the mechanisms for the reduction of ketones and other functional groups by LiAlH(4). We have employed a combination of theoretical and experimental techniques to investigate the structure of LiAlH(4) in ethereal solutions. Using complexation agents, we measured the IR spectra of LiAlH(4) and AlH(4)(-) in tetrahydrofuran (THF). Hybrid quantum-classical (QM-MM) simulations have also been carried out to compute the IR spectra of associated and dissociated LiAlH(4) species and the free-energy profile for the dissociation process in solution. Our experimental estimate of the dissociation constant in THF is 0.021 +/- 0.002, while the predicted computational value corresponding to a model dimethyl ether solvent is 0.001. The free-energy profile shows only one minimum corresponding to a contact ion pair at a Li-Al separation distance of 3.0 A. These results are consistent with the fact that LiAlH(4) is essentially associated in ethereal solutions forming contact ion pairs.
Aluminum Compounds↗
The mechanism for water exchange in [UO(2)(H(2)O)(5)](2+) and [UO(2)(oxalate)(2)(H(2)O)](2-), as studied by quantum chemical methods.
The mechanisms for the exchange of water between [UO(2)(H(2)O)(5)](2+), [UO(2)(oxalate)(2)(H(2)O)](2)(-)(,) and water solvent along dissociative (D), associative (A) and interchange (I) pathways have been investigated with quantum chemical methods. The choice of exchange mechanism is based on the computed activation energy and the geometry of the identified transition states and intermediates. These quantities were calculated both in the gas phase and with a polarizable continuum model for the solvent. There is a significant and predictable difference between the activation energy of the gas phase and solvent models: the energy barrier for the D-mechanism increases in the solvent as compared to the gas phase, while it decreases for the A- and I-mechanisms. The calculated activation energy, Delta U(++), for the water exchange in [UO(2)(H(2)O)(5)](2+) is 74, 19, and 21 kJ/mol, respectively, for the D-, A-, and I-mechanisms in the solvent, as compared to the experimental value Delta H(++) = 26 +/- 1 kJ/mol. This indicates that the D-mechanism for this system can be ruled out. The energy barrier between the intermediates and the transition states is small, indicating a lifetime for the intermediate approximately 10(-10) s, making it very difficult to distinguish between the A- and I-mechanisms experimentally. There is no direct experimental information on the rate and mechanism of water exchange in [UO(2)(oxalate)(2)(H(2)O)](2-) containing two bidentate oxalate ions. The activation energy and the geometry of transition states and intermediates along the D-, A-, and I-pathways were calculated both in the gas phase and in a water solvent model, using a single-point MP2 calculation with the gas phase geometry. The activation energy, Delta U(++), in the solvent for the D-, A-, and I-mechanisms is 56, 12, and 53 kJ/mol, respectively. This indicates that the water exchange follows an associative reaction mechanism. The geometry of the A- and I-transition states for both [UO(2)(H(2)O)(5)](2+) and [UO(2)(oxalate)(2)(H(2)O)](2-) indicates that the entering/leaving water molecules are located outside the plane formed by the spectator ligands.
Journal Article↗
A priori assessment of the stereoelectronic profile of phosphines and phosphites.
This research has demonstrated the utility of a rigorously calibrated, molecular mechanics/semiempirical quantum mechanical protocol for developing stereoelectronic (Tolman) maps for phosphine ligands. A computational analysis of alkyl and aryl phosphines in common usage suggests that these ligands are quite similar stereoelectronically. A noticeable gap in the Tolman map for common phosphines is observed for large, electron-poor phosphines. Several candidates meeting these criteria were identified, the most promising of which is P(t-C(4)F(9))(3). Phosphines in which the phosphorus participates in a ring, which comprise a very small subset of reported phosphines, have very interesting stereoelectronic properties, particularly those in which the ligating phosphorus is part of a three-membered ring. In terms of steric properties, the symmetric deformation coordinate proposed by Orpen and co-workers on the basis of crystallographic studies is calculated with sufficient accuracy using PM3(tm) to allow good confidence in predictions of novel phosphines. For quantification of the electronic properties of phosphines, we analyzed changes in the CO stretching frequency upon changing the ancillary phosphine ligands.
Journal Article↗
Theoretical perspectives on the reaction mechanism of serine proteases: the reaction free energy profiles of the acylation process.
The reaction mechanism of serine proteases (trypsin), which catalyze peptide hydrolysis, is studied theoretically by ab initio QM/MM electronic structure calculations combined with Molecular Dynamics-Free Energy Perturbation calculations. We have calculated the entire reaction free energy profiles of the first reaction step of this enzyme (acylation process). The present calculations show that the rate-determining step of the acylation is the formation of the tetrahedral intermediate, and the breakdown of this intermediate has a small energy barrier. The calculated activation free energy for the acylation is approximately 17.8 kcal/mol at QM/MM MP2/(aug)-cc-pVDZ//HF/6-31(+)G/AMBER level, and this reaction is an exothermic process. MD simulations of the enzyme-substrate (ES) complex and the free enzyme in aqueous phase show that the substrate binding induces slight conformational changes around the active site, which favor the alignment of the reactive fragments (His57, Asp102, and Ser195) together in a reactive orientation. It is also shown that the proton transfer from Ser195 to His57 and the nucleophilic attack of Ser195 to the carbonyl carbon of the scissile bond of the substrate occur in a concerted manner. In this reaction, protein environment plays a crucial role to lowering the activation free energy by stabilizing the tetrahedral intermediate compared to the ES complex. The polarization energy calculations show that the enzyme active site is in a very polar environment because of the polar main chain contributions of protein. Also, the ground-state destabilization effect (steric strain) is not a major catalytic factor. The most important catalytic factor of stabilizing the tetrahedral intermediate is the electrostatic interaction between the active site and particular regions of protein: the main chain NH groups in Gly193 and Ser195 (so-called oxyanion hole region) stabilize negative charge generated on the carbonyl oxygen of the scissile bond, and the main chain carbonyl groups in Ile212 approximately Ser214 stabilize a positive charge generated on the imidazole ring of His57.
Binding Sites↗
Theoretical evidence for enhanced NO dimerization in aromatic hosts: implications for the role of the electrophile (NO)(2) in nitric oxide chemistry.
Nitric oxide dimerization in gas phase and aromatic hosts (benzene) has been investigated with ab initio quantum mechanics. Using the (RO)MP2-aug-cc-pVDZ method, the computed bond dissociation energy (ON...NO) and geometry of (NO)2 in the gas phase are consistent with the reported spectroscopic data. A relatively strong interaction (-5.4 kcal/mol) between (NO)2 and benzene indicates that aromatic surrounding enhances the NO dimerization. Calculations on reactions of phosphine and methanethiol with NO and (NO)2 show that the dimer is much more reactive. This explains reactions of NO with phosphines and thiols.
Benzene↗
Anisotropic local motions and location of amide protons in proteins.
A new method has been developed to obtain dynamic and structural information about peptide planes in proteins by a combination of measurements of weak short-range cross-correlation rates R(H(N)N/NC') that are due to concerted fluctuations of the H(N)-N and N-C' dipole-dipole interactions and stronger long-range cross-correlation rates R(C'H(N)/H(N)N) and R(NH(N)/H(N)C(alpha)). The rates were interpreted using the axially symmetric Gaussian axial fluctuation model (GAF). The oscillation amplitudes as well as the positions of H(N) atoms with respect to peptide planes in ubiquitin were determined. Most N-H(N) bonds were found not to lie exactly along the bisector of the N-C' and N-C(alpha) bonds but to be slightly tilted toward the carbon-terminal side of the peptide.
Amides↗
Modeling the anticancer action of some retinoid compounds by making use of the OASIS method.
The powerful OASIS (optimized approach based on structural indices set) approach is applied to the anticancer activity of a series of vitamin A analogs. The best three- and four-variable models obtained via the OASIS technique have correlation coefficients of 0.973 vs. 0.990 and standard deviations s2 = 0.11 and 0.05, respectively. The models incorporate the hydrophobicity factor log P, two geometric parameters (topological indices and/or 3-D steric ones), and the molecular dipole moment. For a set of 15 compounds studied here, the activity measured by ED50 was well correlated by models with approximately equal contribution of the through cell membrane transport and the geometric drug-receptor correspondence while weak nonspecific electronic interaction was also found to play some role. Comparison to previous treatments of this data is given and extension to larger sets is discussed.
Antineoplastic Agents↗
Stereoselective characterization of the 1,4-dihydropyridine binding site at L-type calcium channels in the resting state and the opened/inactivated state.
Via a 3D-QSAR pseudoreceptor modeling approach, atomistic binding site models for pharmacologically active 1,4-dihydropyridines (DHPs) were developed. Applying a training set of pure DHP enantiomers a pseudoreceptor model representing the resting state of voltage-gated calcium channels (VGCCs) was generated by correlating experimental versus predicted free energies of binding (DeltaG degrees). For validation further test set derivatives-not used for receptor generation-were predicted yielding root-mean-square (rms) deviation of 0.532 kcal/mol. Selectivity of the resting state model was checked by using the same DHP training set compounds but experimental data for the inactivated channel mode. Although there was found an almost perfect correlation for the training set, the following free relaxation of the corresponding test set applying a Monte Carlo protocol showed rms of 2.033 kcal/mol, clearly demonstrating the lack of any predicting character of the hybrid model. Taking into consideration 19 additional nifedipine analogues, a further verification of the model was performed. This yielded a good correlation for the 12 training set compounds and a satisfactory prediction for the test set molecules with rms of 0.409 kcal/mol. The generation of a pseudoreceptor model depicting the opened/inactivated state of VGCCs required one single additional residue to achieve a rms of 0.848 kcal/mol for the prediction of the test set derivatives. Since all pseudoreceptor models are composed of the same six amino acid residues-Thr, Phe, Gly, Met, Tyr, Tyr-transition from resting to open/inactivated state may be described by one additional hydrogen bond donor interaction (Thr) at the left-hand side of DHPs. Furthermore, a potential charge-transfer interaction for all electron-deficient 4-phenyl DHPs is postulated, because significant correlation between quantum chemically AM1 (R = 0.91) and RHF 6-31G (R = 0.84) computed LUMO energies and experimentally detected DeltaG degrees exp values was found.
Binding Sites↗
On the structure and relative stability of C50 fullerenes.
The complete set of 271 classical fullerene isomers of C50 has been studied by full geometry optimizations at the SAM1, PM3, AM1, and MNDO quantum-chemical levels, and their lower energy structures have also been partially computed at the ab initio levels of theory. A D(5h) species, with the least number of pentagon adjacency, is predicted by all semiempirical methods and the HF/4-31G calculations as the lowest energy structure, but the B3LYP/6-31G* geometry optimizations favor a D3 structure (with the largest HOMO-LUMO gap and the second least number of adjacent pentagons) energetically lower (-2 kcal/mol) than the D(5h) isomer. To clarify the relative stabilities at elevated temperatures, the entropy contributions are taken into account on the basis of the Gibbs energy at the HF/4-31G level for the first time. The computed relative-stability interchanges show that the D3 isomer behaves more thermodynamically stable than the D(5h) species within a wide temperature interval related to fullerene formation. According to a newly reported experimental observation, the structural/energetic properties and relative stabilities of both critical isomers (D(5h) and D3) are analyzed along with the experimentally identified decachlorofullerene C50Cl10 of D(5h) symmetry. Some features of higher symmetry C50 nanotube-type isomers are also discussed.
Journal Article↗
Interior and interfacial aqueous solvation of benzene dicarboxylate dianions and their methylated analogues: A combined molecular dynamics and photoelectron spectroscopy study.
Aqueous solvation of benzene dicarboxylate dianions (BCD(2-)) was studied by means of photoelectron spectroscopy and molecular dynamics simulations. Photoelectron spectra of hydrated o- and p-BCD(2-) with up to 25 water molecules were obtained. An even-odd effect was observed for the p-BCD(2-) system as a result of the alternate solvation of the two negative charges. However, the high polarizability of the benzene ring makes the two carboxylate groups interact with each other in p-BCD(2-), suppressing the strength of this even-odd effect compared with the linear dicarboxylate dianions linked by an aliphatic chain. No even-odd effect was observed for the o-BCD(2-) system, because each solvent molecule can interact with the two carboxylate groups at the same time due to their proximity. For large solvated clusters, the spectral features of the solute decreased while the solvent features became dominant, suggesting that both o- and p-BCD(2-) are situated in the center of the solvated clusters. Molecular dynamics simulations with both nonpolarizable and polarizable force fields confirmed that all three isomers (o-, m-, and p-BCD(2-)) solvate in the aqueous bulk. However, upon methylation the hydrophobic forces overwhelm electrostatic interactions and, as a result, the calculations predict that the tetramethyl-o-BCD(2-) is located at the water surface with the carboxylate groups anchored in the liquid and the methylated benzene ring tilted away from the aqueous phase.
Anions↗
Concentration-dependent frequency shifts and Raman spectroscopic noncoincidence effect of the C=O stretching mode in dipolar mixtures of acetone/dimethyl sulfoxide. Experimental, theoretical, and simulation results.
The nu(C=O) Raman band frequencies of acetone have been analyzed to separate the contributions of the environmental effect and the vibrational coupling to the gas-to-liquid frequency shifts of this band and to elucidate the changes in these two contributions upon dilution in DMSO. We have measured the frequencies of the nu((12)C=O) band in acetone/DMSO binary mixtures, the nu((13)C=O) band of the acetone-(13)C=O present as a natural abundance isotopic impurity in these mixtures, and both the nu((12)C=O) and nu((13)C=O) bands in the acetone-(12)C=O/acetone-(13)C=O isotopic mixtures at infinite dilution. These frequencies are compared with those of the nu((12)C=O) band in the acetone/CCl(4) binary mixtures measured previously. We have found the following three points: (i) The negative environmental contribution for the nu((12)C=O) oscillator of acetone completely surrounded by DMSO is reduced in magnitude by +5.5 cm(-1) and +7.8 cm(-1) upon the complete substitution of DMSO with acetone and CCl(4) molecules, respectively, indicating the progressive reduction of the attractive forces exerted by the environment on the nu((12)C=O) mode of acetone. (ii) In DMSO and other solvents, the contribution of the vibrational coupling to the frequency of the isotropic Raman nu((12)C=O) band of acetone becomes progressively more negative with increasing acetone concentration up to a value of -5.5 cm(-1), while the contribution to the frequency of the anisotropic Raman band remains approximately unchanged. The only difference resides in the curvatures of the concentration dependencies of these contributions which depend on the relative solute/solvent polarity. (iii) The noncoincidence effect (separation between the anisotropic and isotropic Raman band frequencies) of the nu(C=O) mode in the acetone/DMSO mixtures exhibits a downward (concave) curvature, in contrast to that in the acetone/CCl(4) mixtures, which shows an upward (convex) curvature. This result is supported by MD simulations and by theoretical predictions and is interpreted as arising from the reduction and enhancement of the short-range orientational order of acetone in the acetone/DMSO and acetone/CCl(4) mixtures, respectively.
Acetone↗