AM1 Hamiltonian Research Articles

19F-nuclear magnetic resonance spectroscopy as a tool to investigate host-guest complexation of some antidepressant drugs with natural and modified cyclodextrins

Purpose: 19 F-Nuclear magnetic resonance spectroscopy ( 19 F-NMR) was used to study host-guest complexation of three fluorine containing antidepressant drugs, viz, fluoxetine hydrochloride, citalopram hydrobromide and fluvoxamine maleate, with various cyclodextrins (CD), including α-, β-cyclodextrin, methylated α-cyclodextrin (M-α-CD), diamino derivative of methylated α-cyclodextrin, (DAM-α-CD) and tetramino derivative of methylated α-cyclodextrin (TAM-α-CD). Methods: Using the mole ratio method, a 1:1 stoichiometry was determined for the resulting inclusion complexes. 19 F chemical shifts were used to determine the formation constant of the complexes. Experiments were performed with solutions containing 0.001 M drug and various concentrations of CDs. NMR data were plotted as 19 F chemical shift versus CD/drug mole ratio, and fitted using the nonlinear least-squares curve fitting program, KINFIT, to obtain the formation constant of CD-drug complex. Molecular modeling (MM) calculations were used to predict the geometry of the complex of fluvoxamine and β-CD. Molecular modeling studies were performed in vacuum phase, employing empirical force fields and semi-empirical quantum theory using AM1 Hamiltonian. Results: Complex formation caused separation of the fluorine peaks that can be assigned to the two enantiomers of fluoxetine hydrochloride. Molecular modeling data suggest that fluvoxamine/β-CD inclusion complexes have a 1:1 stoichiometry and that the CF3-substituted ring of fluvoxamine is embedded in the cavity of β-CD, indicating a good agreement between molecular modeling calculation and experimental data (NMR data). Conclusion: One-dimensional 19 F-NMR is a fast and convenient method for the determination of complex stoichiometry and complexation constants of natural and modified CDs and fluorinated drugs. Keywords: Antidepressant drugs, Cyclodextrins, Complexation, Inclusion complex, Formation constant, 19 F-NMR

Computational Study of the Degradation of S-Adenosyl Methionine in Water.

The degradation of S-adenosyl methionine (SAM) to homoserine-γ-lactone (HSL) and methyltioadenine (MTA) in water is studied with MD simulations. The AM1 Hamiltonian is used for the quantum part and the flexible AMBER force field for the H2O molecules. The MD simulations predict the free energy barrier for the degradation reaction to be between 109 and 112 kJ mol-1 and an overall gain in free energy of -26 kJ mol-1. The high barrier and the low energy gain of this reaction can be linked to interactions among the carboxylate group of the SAM molecule and solvent H2O molecules, which are not observed on the product side. Hence, the H2O molecules effectively slow down the reaction that otherwise would be much faster.

Theoretical and experimental studies on the corrosion inhibition potentials of some purines for aluminum in 0.1 M HCl

Experimental aspect of the corrosion inhibition potential of adenine (AD), guanine (GU) and, hypoxanthine (HYP) was carried out using weight loss, potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) methods while the theoretical aspect of the work was carried out by calculations of semi-empirical parameters (for AM1, MNDO, CNDO, PM3 and RM1 Hamiltonians), Fukui functions and inhibitor–metal interaction energies. Results obtained from the experimental studies were in good agreement and indicated that adenine (AD), guanine (GU) and hypoxanthine (HYP) are good adsorption inhibitors for the corrosion of aluminum in solutions of HCl. Data obtained from electrochemical experiment revealed that the studied purines functioned by adsorption on the aluminum/HCl interface and inhibited the cathodic half reaction to a greater extent and anodic half reaction to a lesser extent. The adsorption of the purines on the metal surface was found to be exothermic and spontaneous. Deviation of the adsorption characteristics of the studied purines from the Langmuir adsorption model was compensated by the fitness of Flory Huggins and El Awardy et al. adsorption models. Quantum chemical studies revealed that the experimental inhibition efficiencies of the studied purines are functions of some quantum chemical parameters including total energy of the molecules (TE), energy gap (EL–H), electronic energy of the molecule (EE), dipole moment and core–core repulsion energy (CCR). Fukui functions analysis through DFT and MP2 theories indicated slight complications and unphysical results. However, results obtained from calculated Huckel charges, molecular orbital and interaction energies, the adsorption of the inhibitors proceeded through the imine nitrogen (N5) in GU, emanine nitrogen (N7) in AD and the pyridine nitrogen (N5) in HPY.

Semiempirical Quantum Chemical Calculations Accelerated on a Hybrid Multicore CPU-GPU Computing Platform.

In this work, we demonstrate that semiempirical quantum chemical calculations can be accelerated significantly by leveraging the graphics processing unit (GPU) as a coprocessor on a hybrid multicore CPU-GPU computing platform. Semiempirical calculations using the MNDO, AM1, PM3, OM1, OM2, and OM3 model Hamiltonians were systematically profiled for three types of test systems (fullerenes, water clusters, and solvated crambin) to identify the most time-consuming sections of the code. The corresponding routines were ported to the GPU and optimized employing both existing library functions and a GPU kernel that carries out a sequence of noniterative Jacobi transformations during pseudodiagonalization. The overall computation times for single-point energy calculations and geometry optimizations of large molecules were reduced by one order of magnitude for all methods, as compared to runs on a single CPU core.

Convergence of QM/MM free-energy perturbations based on molecular-mechanics or semiempirical simulations

Lately, there has been great interest in performing free-energy perturbation (FEP) at the combined quantum mechanics and molecular mechanics (QM/MM) level, e.g. for enzyme reactions. Such calculations require extensive sampling of phase space, which typically is prohibitive with density-functional theory or ab initio methods. Therefore, such calculations have mostly been performed with semiempirical QM (SQM) methods, or by using a thermodynamic cycle involving sampling at the MM level and perturbations between the MM and QM/MM levels of theory. However, the latter perturbations typically have convergence problems, unless the QM system is kept fixed during the simulations, because the MM and QM/MM descriptions of the internal degrees of freedom inside the QM system are too dissimilar. We have studied whether the convergence of the MM → QM/MM perturbation can be improved by using a thoroughly parameterised force field or by using SQM/MM methods. As a test case we use the first half-reaction of haloalkane dehalogenase and the QM calculations are performed with the PBE, B3LYP, and TPSSH density-functional methods. We show that the convergence can be improved with a tailored force field, but only locally around the parameterised state. Simulations based on SQM/MM methods using the MNDO, AM1, PM3, RM1, PDDG-MNDO, and PDDG-PM3 Hamiltonians have slightly better convergence properties, but very long simulations are still needed (~10 ns) and convergence is obtained only if electrostatic interactions between the QM system and the surroundings are ignored. This casts some doubts on the common practice to base QM/MM FEPs on semiempirical simulations without any reweighting of the trajectories.

Designing Fullerene Separation Materials: A Theoretical Study

Fullerenes, among other carbon nanostructures, are very promising as potential components for the development of nanodevices and nanomachines. One of the current hurdles in developing such devices is obtaining components/molecules of the same size in sufficient quantity. Typically, when carbon nanostructures are synthesized, a distribution of sizes is generated. Therefore, an efficient separation technique is needed. A computational model that could identify suitable separation materials would be of considerable value. Herein, we apply the AM1-FS1 method, an empirically corrected version of the AM1 Hamiltonian, to study the complexation of eight different fullerenes by four different polycyclic aromatic hydrocarbon nanorings. We find (not unexpectedly) that the diameter of the nanoring governs the expected guest; however, two different size fullerenes may adopt conformations with a common diameter, eliminating selectivity. Therefore, selective separation of fullerenes is a conformation problem, with increasing prevalence as the size of the fullerenes increase.

Prediction of the Dissociation Constant pKa of Organic Acids from Local Molecular Parameters of Their Electronic Ground State

A quantum chemical method has been developed to estimate the dissociation constant pK(a) of organic acids from their neutral molecular structures by employing electronic structure properties. The data set covers 219 phenols (including 29 phenols with intramolecular H-bonding), 150 aromatic carboxylic acids, 190 aliphatic carboxylic acids, and 138 alcohols, with pK(a) varying by 16 units (0.38-16.80). Optimized ground-state geometries employing the semiempirical AM1 Hamiltonian have been used to quantify the site-specific molecular readiness to donate or accept electron charge in terms of both charge-associated energies and energy-associated charges, augmented by an ortho substitution indicator for aromatic compounds. The resultant regression models yield squared correlation coefficients (r(2)) from 0.82 to 0.90 and root-mean-square errors (rms) from 0.39 to 0.70 pK(a) units, corresponding to an overall (subset-weighted) r(2) of 0.86. Simulated external validation, leave-10%-out cross-validation and target value scrambling demonstrate the statistical robustness and prediction power of the derived model suite. The low intercorrelation with prediction errors from the commercial ACD package provides opportunity for a consensus model approach, offering a pragmatic way for further increasing the confidence in prediction significantly. Interestingly, inclusion of calculated free energies of aqueous solvation does not improve the prediction performance, probably because of the limited precision provided by available continuum-solvation models.

Hydration Free Energies Using Semiempirical Quantum Mechanical Hamiltonians and a Continuum Solvent Model with Multiple Atomic-Type Parameters

To build the foundation for accurate quantum mechanical (QM) simulation of biomacromolecules in an aqueous environment, we undertook the optimization of the COnductor-like Screening MOdel (COSMO) atomic radii and atomic surface tension coefficients for different semiempirical Hamiltonians adhering to the same computational conditions recently followed in the simulation of biomolecular systems. This optimization was achieved by reproducing experimental hydration free energies of a set consisting of 507 neutral and 99 ionic molecules. The calculated hydration free energies were significantly improved by introducing a multiple atomic-type scheme that reflects different chemical environments. The nonpolar contribution was treated according to the scaled particle Claverie-Pierotti formalism. Separate radii and surface tension coefficient sets have been developed for AM1, PM3, PM5, and RM1 semiempirical Hamiltonians, with an average unsigned error for neutral molecules of 0.64, 0.66, 0.73, and 0.71 kcal/mol, respectively. Free energy calculation of each molecule took on average 0.5 s on a single processor. The new sets of parameters will enhance the quality of semiempirical QM calculations using COSMO in biomolecular systems. Overall, these results further extend the utility of QM methods to chemical and biological systems in the condensed phase.

XAFS study of the complex of an acetylacetonate-based ligand and copper ion

An X-ray absorption fine structure (XAFS) study has been conducted to reveal the local structure and chemical state of the copper in the complex of an acetylacetonate-based ligand (L1) and copper ion in acetonitrile solution. The copper ion in the complex was found to be divalent from the Cu K-edge X-ray absorption near-edge structure (XANES) spectrum. The FEFF (ab initio multiple scattering calculations of XAFS) were performed with the model compounds, whose structures were optimized by using MOPAC program with AM1 Hamiltonian. The comparative study of the experimental XAFS spectra and theoretical calculations from FEFF gave the perspectives for clarifying the coordination structure of the complex of L1 and copper ion.

Quasi-classical trajectory study of the dynamics of the Cl + CH4→ HCl + CH3 reaction

We present an on-the-fly classical trajectory study of the Cl + CH(4)→ HCl + CH(3) reaction using a specific reaction parameter (SRP) AM1 Hamiltonian that was previously optimized for the Cl + ethane reaction [S. J. Greaves et al., J. Phys Chem A, 2008, 112, 9387]. The SRP-AM1 Hamiltonian is shown to be a good model for the potential energy surface of the title reaction. Calculated differential cross sections, obtained from trajectories propagated with the SRP-AM1 Hamiltonian compare favourably with experimental results for this system. Analysis of the vibrational modes of the methyl radical shows different scattering distributions for ground and vibrationally excited products.

Photochemistry of DNA Fragments via Semiclassical Nonadiabatic Dynamics

Forming upon absorption of a UV photon, excited states of DNA are subject to nonadiabatic evolution, via either internal conversion (IC) back to the ground state or mutagenesis. Nonadiabatic processes following the formation of the first singlet excited states, S1, in 10 different small DNA fragments--4 single 4'H-nucleosides, 2 Watson-Crick base pairs, and 4 nucleotide quartets--have been investigated. Simulations were done via the nonadiabatic direct trajectory surface hopping semiclassical dynamics. The electronic wave function was obtained with configuration interaction, based on the semiempirical AM1 and PM3 Hamiltonians with fractional orbital occupation numbers. The evolution of the electronic wave function was governed by the time-dependent Schrödinger equation with a locally diabatic representation, intrinsically stable near surface crossings. The nuclei evolved on adiabatic potential energy surfaces, as prescribed by classical Newtonian dynamics, with sudden hops between potential energy surfaces to account for nonadiabatic transitions. The "fewest switches" surface hopping algorithm coupled the quantum and classical parts of the system. The dynamics simulations revealed several routes of nonadiabatic relaxation in these systems, which were not reported previously, and also recovered known routes of IC.

Density Functional Theory Based Quantitative Structure Activity Relationship Study of 2,5-Bis(1-Aziridinyl)-p-Benzoquinones with Lymphoid Leukemia

Problem statement: QSAR techniques increase the probability of success and reduce time and coast in drug discovery process. The study presented QSAR investigation on 32 bioactive aziridinylbenzoquinones that have activity against lymphoid leukemia. Approach: Molecular descriptors, molecular weight, total energy, hardness, chemical potential, electrophilicity index, HOMO and LUMO energies were calculated. Initial geometry optimizations were carried out with the AM1 Hamiltonian. The lowest energy conformations were subjected to single point calculations by the DFT method by employing Beck's Three-Parameter hybrid functional (B3LYP) and pvDZ basis set. Several models for the prediction of biological activity have been drawn up by using the multiple regression technique. Results: A model with hapta parametric linear equation with R2 value of 0.886 was presented. Conclusion: The biological activity of the studied compounds can be modeled with quantum chemical molecular descriptors.

A New Empirical Correction to the AM1 Method for Macromolecular Complexes.

Modeling systems that are governed by van der Waals (dispersion) interactions using empirically corrected DFT methods is becoming increasingly popular due to the promise of a CCSD(T) level accuracy at the computational cost of DFT. Although, DFT methods are computationally efficient in comparison to the CCSD(T) method, currently, structural optimizations using DFT methods are generally only feasible for systems of less than a few hundred atoms. We seek a method applicable to macromolecular complexes. In order to model such large systems, empirically corrected semiempirical methods appear to be an attractive alternative. As with most common DFT methods, the popular semiempirical methods (e.g., AM1) also do not model long-range dispersion (and therefore an empirical correction term is desirable), but this is not their only shortcoming. For weakly interacting systems, hydrogen bonding also poses a concern. A new empirically corrected AM1 method that uses two empirical correction terms, one for dispersion and one for hydrogen bonding interactions, is presented and termed AM1-FS1. This new empirically corrected AM1 method has been parametrized to a diverse training set of 66 complexes that includes nonequilibrium structures and yields sub-kilocalorie accuracy in the prediction of intermolecular interaction energies. More significantly, AM1-FS1 achieves this result with substantially less parametrization than existing empirically corrected semiempirical methods and without modification of the original AM1 parameters so that it retains both the computational efficiency and predictive power for thermo-chemical quantities of the original AM1 Hamiltonian. The performance of AM1-FS1 is also tested on several carbon nanostructure complexes and pseudorotaxanes and is found to produce results in very good agreement with the best first-principles calculations.

Modelling dissociation constants of organic acids by local molecular parameters

The dissociation constant pKa defines the ionization degree of organic compounds. It is an important parameter that affects their toxicity and environmental behavior and fate. Among the present approaches to predict pKa values of organic chemicals, increment methods show a good performance but are limited by missing values of special groups. The purpose of this study is to develop models for predicting the pKa of organic acids directly from their molecular structures. A quantum chemical method was introduced by employing local molecular parameters. Experimental pKa values of more than 1000 organic acids, including phenols, aromatic carboxylic acids, aliphatic carboxylic acids and alcohols were selected, and all molecules were optimized using the semi-empirical AM1 Hamiltonian. Simple models with several descriptors for different subsets were calibrated by multilinear regression (MLR). Substituent positions on aromatic rings were also taken into account. The obtained models yield good predictive squared correlation coefficients q2 and superior performance compared with other quantum chemical models. The prediction capability is further evaluated using cross validation. The models unravel that the potential of oxygen atom conjoint to ionizable hydrogen atom to accept extra electronic charge is the single most important contribution to the dissociation of hydrogen atom. Non-linear statistical analysis methods were also applied because of the non-linear character of the employed descriptors. The study was supported by the China Scholarship Council and by the EU project OSIRIS (IP, contact No. 037017), which is gratefully acknowledged.

Quantum Mechanical Pairwise Decomposition Analysis of Protein Kinase B Inhibitors: Validating a New Tool for Guiding Drug Design

Quantum mechanical semiempirical comparative binding energy analysis calculations have been carried out for a series of protein kinase B (PKB) inhibitors derived from fragment- and structure-based drug design. These protein−ligand complexes were selected because they represent a consistent set of experimental data that includes both crystal structures and affinities. Seven scoring functions were evaluated based on both the PM3 and the AM1 Hamiltonians. The optimal models obtained by partial least-squares analysis of the aligned poses are predictive as measured by a number of standard statistical criteria and by validation with an external data set. An algorithm has been developed that provides residue-based contributions to the overall binding affinity. These residue-based binding contributions can be plotted in heat maps so as to highlight the most important residues for ligand binding. In the case of these PKB inhibitors, the maps show that Met166, Thr97, Gly43, Glu114, Ala116, and Val50, among other residues, play an important role in determining binding affinity. The interaction energy map makes it easy to identify the residues that have the largest absolute effect on ligand binding. The structure−activity relationship (SAR) map highlights residues that are most critical to discriminating between more and less potent ligands. Taken together the interaction energy and the SAR maps provide useful insights into drug design that would be difficult to garner in any other way.

Variation of the Backbone Conjugation in NLO Model Compounds: Torsion‐Angle‐Restricted, Biphenyl‐Based Push‐Pull‐Systems

AbstractTerminal piperidinyl‐ and nitro‐functionalized biphenyls, bridged between the 2 and 2′ positions by a variable number of methylene groups, are synthesized and fully characterized. These push‐pull systems with defined and restricted torsion angles between their phenyl rings are ideal model compounds to investigate the influence of the chromophore's conjugation in nonlinear optic (NLO) responses. A general synthetic route that can be implemented to access these model compounds is reported, starting from dibromo or ditriflate biphenyls. Hartwig–Buchwald cross‐coupling, a selective azacycloalkylation of diaminobiphenyls and a mild oxidation of primary amines to nitro groups in the presence of a tertiary amine summarizes the synthetic pathway towards the desired model compounds. NLO properties of the series of torsionally constrained push‐pull biphenyls are collected by electric‐field‐induced second‐harmonic generation (EFISH) experiments. The results agree qualitatively with semi‐empirical simulations based on the AM1 Hamiltonian. A linear dependence of the quadratic response on the cos2(Φ) of the inter‐aryl dihedral angle is observed, which points to oscillator strength loss as the dominant effect of increasing backbone twist.

Discrete Optimization of Electronic Hyperpolarizabilities in a Chemical Subspace.

We introduce a general optimization algorithm based on an interpolation of property values on a hypercube. Each vertex of the hypercube represents a molecule, while the interior of the interpolation represents a virtual superposition ("alchemical" mutation) of molecules. The resultant algorithm is similar to branch-and-bound/tree-search methods. We apply the algorithm to the optimization of the first electronic hyperpolarizability for several tolane libraries. The search includes structural and conformational information. Geometries were optimized using the AM1 Hamiltonian, and first hyperpolarizabilities were computed using the INDO/S method. Even for small libraries, a significant improvement of the hyperpolarizability, up to a factor of ca. 4, was achieved. The algorithm was validated for efficiency and reproduced known experimental results. The algorithm converges to a local optimum at a computational cost on the order of the logarithm of the library size, making large libraries accessible. For larger libraries, the improvement was accomplished by performing electronic structure calculations on less than 0.01% of the compounds in the larger libraries. Alternation of electron donating and accepting groups in the tolane scaffold was found to produce candidates with large hyperpolarizabilities consistently.

Synthesis, spectral and computational studies of some N-acyl-t(3)-isopropyl-r(2),c(6)-bis-2′-furylpiperidin-4-one oximes

Four N-acyl-t(3)-isopropyl-r(2),c(6)-bis-2'-furylpiperidin-4-one oximes 1-4 were synthesized and the high resolution (1)H and (13)C NMR spectra have been recorded at various temperatures and analyzed. The spectra reveal the presence of two rotameric forms (syn and anti) in solution. (1)H-(1)H COSY and (1)H-(13)C COSY spectra have been recorded to assist the assignment of the signals for the syn and anti isomers of 1-4. Coupling constants predict an equilibrium mixture of boat form B(1) and alternate chair form CA for 1-4. The effect of varying the substituents at nitrogen and at C(4) on the (1)H and (13)C chemical shifts has been analyzed in detail. The molecular structures of the N-acyl derivatives 1-4 were also determined using AM1 Hamiltonian and the results have been compared to the results derived from spectral studies. Mass spectra have also been recorded for 1-4.

Theoretical prediction for the infinite dilution activity coefficients of organic compounds in ionic liquids

On the basis of the theoretical linear solvation energy relationship (TLSER) suggested by Wilson et al. and the quantum chemical descriptors computed by AM1 Hamiltonian, a predicting model was developed to characterize the activity coefficients at infinite dilution γi∞ of 34 organic solutes in ionic liquids (ILs) 1-butyl-3-methylimidazolium trifluoromethanesulfonate ([BMIM][CF3SO3]) and 1-propyl-2,3-dimethylimidazolium tetrafluoroborate ([PDMIM][BF4]) at 323.15 K. The results showed that the model had an good correlation and could successfully describe γi∞. In addition, correlation parameters are analyzed to understand the interactions that affect infinite dilution activity coefficients.

First hyperpolarizability of donor-acceptor substituted aromatic backbone molecular systems: Effect of dihedral angle and excitation energy

Charge transfer molecular systems that contain two fused benzene rings as the core have been studied for their contribution to the first order hyperpolarizability β. Two identical donor groups are attached through the core to two cyanide groups that act as acceptors. Calculation of β has been done using ab-initio HF and semi-empirical AM1 Hamiltonian. The effect of twist (dihedral) angle t on β and HOMO-LUMO energy gap has been analyzed using both the methods. Inverse relationship between HOMO-LUMO energy gap and β is observed from their variation with the dihedral angle only in the case of AM1. It is clear from the study that a planar geometry is not an essential condition for a large value of β. Dispersion plots show the first excitation energy values for all the molecules using AM1 and HF/6-31+G(d,p). These plots show a dip in the first excitation peak for AM1. This feature is also observed in the frequency-dependent β calculated by the same method for the equivalent single-core molecules. The first excitation energy values with AM1 calculations are comparable to HF/6-31G(d) but different from HF/6-31+G(d,p). However, the calculation of β using ab-initio Hartree-Fock method does not show the double peak feature, thus providing a clue about the robustness of the model and the influence of basis set in calculating β.