Ab Initio Molecular Orbital Methods Research Articles

Prediction of cyclin-dependent kinase 2 inhibitor potency using the fragment molecular orbital method.

BackgroundThe reliable and robust estimation of ligand binding affinity continues to be a challenge in drug design. Many current methods rely on molecular mechanics (MM) calculations which do not fully explain complex molecular interactions. Full quantum mechanical (QM) computation of the electronic state of protein-ligand complexes has recently become possible by the latest advances in the development of linear-scaling QM methods such as the ab initio fragment molecular orbital (FMO) method. This approximate molecular orbital method is sufficiently fast that it can be incorporated into the development cycle during structure-based drug design for the reliable estimation of ligand binding affinity. Additionally, the FMO method can be combined with approximations for entropy and solvation to make it applicable for binding affinity prediction for a broad range of target and chemotypes.ResultsWe applied this method to examine the binding affinity for a series of published cyclin-dependent kinase 2 (CDK2) inhibitors. We calculated the binding affinity for 28 CDK2 inhibitors using the ab initio FMO method based on a number of X-ray crystal structures. The sum of the pair interaction energies (PIE) was calculated and used to explain the gas-phase enthalpic contribution to binding. The correlation of the ligand potencies to the protein-ligand interaction energies gained from FMO was examined and was seen to give a good correlation which outperformed three MM force field based scoring functions used to appoximate the free energy of binding. Although the FMO calculation allows for the enthalpic component of binding interactions to be understood at the quantum level, as it is an in vacuo single point calculation, the entropic component and solvation terms are neglected. For this reason a more accurate and predictive estimate for binding free energy was desired. Therefore, additional terms used to describe the protein-ligand interactions were then calculated to improve the correlation of the FMO derived values to experimental free energies of binding. These terms were used to account for the polar and non-polar solvation of the molecule estimated by the Poisson-Boltzmann equation and the solvent accessible surface area (SASA), respectively, as well as a correction term for ligand entropy. A quantitative structure-activity relationship (QSAR) model obtained by Partial Least Squares projection to latent structures (PLS) analysis of the ligand potencies and the calculated terms showed a strong correlation (r2 = 0.939, q2 = 0.896) for the 14 molecule test set which had a Pearson rank order correlation of 0.97. A training set of a further 14 molecules was well predicted (r2 = 0.842), and could be used to obtain meaningful estimations of the binding free energy.ConclusionsOur results show that binding energies calculated with the FMO method correlate well with published data. Analysis of the terms used to derive the FMO energies adds greater understanding to the binding interactions than can be gained by MM methods. Combining this information with additional terms and creating a scaled model to describe the data results in more accurate predictions of ligand potencies than the absolute values obtained by FMO alone.

Theoretical Study of Hydrogen Chemisorption to Nitrogen-Substituted Graphene-Like Compounds

Abstract Interaction between nitrogen-substituted graphene-like compounds and hydrogen was investigated using ab initio molecular orbital methods to assess hydrogen storage. We adopted coronene as a model molecule for fragmented graphene-like carbon materials and compared the chemisorption energies of hydrogen on pure and N-substituted coronens by changing nitrogen positions. Among the assumed 19 N-substituted models with different substitution sites, three representative models were selected and closely examined to reveal the dependences on both nitrogen-substitution and hydrogen-adsorption positions. Optimized structures of the chemisorbed products are largely stabilized by N-substitution at a certain position. Positive or negative energy gain was apparent depending on both substituted sites of N and adsorbing position of H2. The results suggest that it is possible to improve hydrogen storage properties of graphene-like materials by N-substitution.

A theoretical study on excited state double proton transfer reaction of a 7-azaindole dimer: an ab initio potential energy surface and its empirical valence bond model

Double proton transfer (DPT) reaction of a 7-azaindole dimer in the first ππ* electronically excited state was studied theoretically. We investigated the reaction mechanism through constructing a full dimensional empirical valence bond potential energy function (PEF) based on potential energies evaluated by ab initio molecular orbital methods, and carrying out quantum dynamics calculations with the PEF. Potential energy surfaces of the DPT obtained at the multi-reference perturbation level of theory favors a concerted DPT mechanism, although a stepwise channel is suggested to open for an excited initial vibrational state. Reduced two dimensional quantum dynamics calculations for a reaction surface Hamiltonian of DPT coordinates were performed. Time constants of the reaction were evaluated to be on the order of picoseconds, which is consistent with experiments. On the other hand, the computed kinetic isotope effect deviates from experimental evidence, suggesting the importance of intermolecular stretching motion, which is not explicit in the present calculations for the quantum effect.

Specific interactions between aryl hydrocarbon receptor and dioxin congeners: Ab initio fragment molecular orbital calculations

Aryl hydrocarbon receptor (AhR) is a transcription factor and its function is activated by the binding of halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 1,2,4-trichlorodibenzo-p-dioxin (TrCDD). TCDD is highly toxic to rat, whereas its congener TrCDD shows only a weak effect on gene expression. In order to elucidate the reason of this remarkable difference in the effect of TCDD and TrCDD, we here obtained stable structures of the complexes with rat AhR (rAhR) and TCDD/TrCDD and investigated their electronic properties by using the ab initio fragment molecular orbital (FMO) method. The results indicate that TCDD binds more strongly to rAhR than TrCDD, which is consistent with the experimentally observed toxicity of TCDD and TrCDD. Furthermore, ab initio FMO calculations elucidate that His324 and Gln381 of rAhR are important for binding TCDD, while His324 and Ser334 are important for TrCDD binding.

Interactions between 1α,25(OH) 2D 3 and residues in the ligand-binding pocket of the vitamin D receptor: A correlated fragment molecular orbital study

To provide physicochemical insight into the role of each residue in the ligand-binding pocket (LBP) of the vitamin D receptor (VDR), we evaluated the energies of the interactions between the LBP residues and 1α,25(OH) 2D 3 by using an ab initio fragment molecular orbital (FMO) method at the Møller–Plesset second-order perturbation (MP2) level. This FMO-MP2 method can be used to correctly evaluate both electrostatic and van der Waals dispersion interactions, and it affords these interaction energies separately. We deduced the nature of each interaction and determined the importance of all the LBP residues involved in ligand recognition by the VDR. We previously reported the results of alanine-scanning mutational analysis (ASMA) of all 34 non-alanine residues lining the LBP of the human VDR. The theoretical results in combination with the ASMA results enabled us to assign the role of each LBP residue. We concluded that electrostatic interactions are the major determinant of the ligand-binding activity and ligand recognition specificity and that van der Waals interactions are important for protein folding and, in turn, for cofactor binding.

Theoretical Study on Reaction Mechanisms and Kinetics of Cyanomidyl Radical with NO

The mechanisms and kinetics of the reaction of the cyanomidyl radical (HNCN) with the NO have been investigated by the high-level ab initio molecular orbital method in conjunction with VTST and RRKM theory. The species involved have been optimized at the B3LYP/6-311++G(3df,2p) level and their single-point energies are refined by the CCSD(T)/aug-cc-PVQZ//B3LYP/6-311++G(3df,2p) method. Our calculated results indicate that the favorable pathways for the formation of several isomers of an HNCN-NO complex. Formations of HNC + N(2)O (P1) and HNCO + N(2) (P2) are also possible, although these two pathways involve little activation energy. Employing the Fukui functions and HSAB theory, we are able to rationalize the scenario of the calculated outcome. The predicted total rate constants, k(total), at a 760 Torr Ar pressure can be represented by the equations k(total) = 4.39 x 10(8) T(-7.30) exp(-1.76 kcal mol(-1)/RT) at T = 298-1000 K and 1.01 x 10(-32) T(5.32) exp(11.27 kcal mol(-1)/RT) at T = 1050-3000 K, respectively, in units of cm(3) molecule(-1) s(-1). In addition, the rate constants for key individual product channels are provided in a table for different temperature and pressure conditions. These results are recommended for combustion modeling applications.

Stereoelectronic interaction effects on the conformational properties of hydrogen peroxide and its analogues containing S and Se atoms: An ab initio, hybrid-DFT study and NBO analysis

Ab initio molecular orbital (MP2/6-311+G**//MP2/6-31G+G**) and hybrid-density functional theory (B3LYP/6-311+G**//MP2/6-311+G**) methods and NBO analysis were used to study the stereoelectronic interaction effects on the conformational properties of hydrogen peroxide ( 1), hydrogen disulfide ( 2) and hydrogen diselenide ( 3). The results showed that the Gibbs free energy difference ( G T − G S ) values at 298.15 K and 1 atm between the skew ( S) and trans ( T) conformations (Δ G T– S ) increase from compound 1 to compound 2 but decrease from compound 2 to compound 3. The C conformations of compounds 1– 3 are less stable than their S and T conformations. Based on these results, the racemization processes of the axial symmetrical ( C 2 symmetry) conformations of compounds 1– 3 take place via their T conformations. Based on the optimized ground state geometries using the MP2/6-311+G** level of theory, the NBO analysis of donor–acceptor (bond–antibond) interactions revealed that the stabilization (resonance) energy associated with LP 2M2 → σ* M3-H4 electronic delocalization for the S conformations of compounds 1– 3 are 1.35, 5.94 and 4.68 kcal mol −1, respectively. There is excellent agreement between the variations of the calculated Δ G T– S and stabilization (resonance) energies associated with LP 2M2→σ* M3-H4 electronic delocalization for the S conformations of compounds 1– 3. The correlations between resonance energies, orbital integrals, dipole moments, bond orders, structural parameters and conformational behaviors of compounds 1– 3 have been investigated. Test were made of complete basis set methods (CBS-QB3, CBS-4 and CBS-Q), the first two gave results essentially indistinguishable from those we used, but the CBS-Q results were in disagreement with experimental and other theoretical results.

A theoretical study of hydrogen adsorption on Li, Be, Na, and Mg atoms attached to aromatic hydrocarbons

The binding energy of a hydrogen molecule on metal atoms (Li, Be, Na, and Mg) attached to aromatic hydrocarbon molecules (benzene and anthracene) was calculated using an ab initio molecular orbital method at the MP2(FC)/cc-pVTZ level with basis set superposition error (BSSE) correction. The energy tended to become more negative as the metal atom had a more positive charge and a smaller radius. The energies of Li2C6H6-H2, Li2C14H10-H2, Na2C14H10-H2, and MgC14H10-H2 were −2.7 to −2.2, −4.0 to −3.1, −2.8 to −0.3, and −1.3 kcal/mol, respectively. Most of these energies were more negative than those on the hydrocarbons without metal atoms (ca. −1 kcal/mol). Analyzing the Lennard–Jones type potential with the parameters determined by the MP2 calculations, it was found that these energies mainly consisted of the induction force caused by the positive charge of the metal atom and the dispersion force from the nearest C6-ring. The energy of BeC14H10-H2 was more negative (−8.6 kcal/mol) than of the other complexes. The hydrogen molecule in this complex had a comparatively longer H–H distance and a more positive H2 charge than the others. These data suggest that the hydrogen adsorption on this complex involves a charge transfer process in addition to physisorption interactions. The hydrogen binding energies in some Li2C14H10-H2 systems (∼−4.0 kcal/mol) and BeC14H10-H2 are promising to operate hydrogen storage/release at ambient temperature with moderate pressure.

Ion Spectroscopy: Where Did It Come From; Where Is It Now; and Where Is It Going?

The ASMS conference on ion spectroscopy brought together at Asilomar on October 16-20, 2009 a large group of mass spectrometrists working in the area of ion spectroscopy. In this introduction to the field, we provide a brief history, its current state, and where it is going. Ion spectroscopy of intermediate size molecules began with photoelectron spectroscopy in the 1960s, while electronic spectroscopy of ions using the photodissociation "action spectroscopic" mode became active in the next decade. These approaches remained for many years the main source of information about ionization energies, electronic states, and electronic transitions of ions. In recent years, high-resolution laser techniques coupled with pulsed field ionization and sample cooling in molecular beams have provided high precision ionization energies and vibrational frequencies of small to intermediate sized molecules, including a number of radicals. More recently, optical parametric oscillator (OPO) IR lasers and free electron lasers have been developed and employed to record the IR spectra of molecular ions in either molecular beams or ion traps. These results, in combination with theoretical ab initio molecular orbital (MO) methods, are providing unprecedented structural and energetic information about gas-phase ions.

Theoretical studies of absorption cross sections for the C̃ B12-X̃ A11 system of sulfur dioxide and isotope effects

The C (1)B(2)-X (1)A(1) photoexcitation of SO(2) was studied to investigate excited-state dynamics and the effects of the initial vibrational state. Ultraviolet photoabsorption cross sections (sigma's) of seven isotopologues ((32)S (16)O(2), (33)S (16)O(2), (34)S (16)O(2), (36)S (16)O(2), (32)S(16)O(17)O, (32)S(16)O(18)O, (34)S(16)O(18)O) were computed using the wave packet propagation technique based on the three-dimensional potential energy surfaces of the X and C states, which were calculated using the ab initio molecular orbital configuration interaction method. Numerous wave packet simulations were carried out under the adiabatic approximation and used to calculate the sigma's of the seven isotopologues at 298 K; we concluded that the absorption spectrum of SO(2) can be reliably modeled within the adiabatic framework based on the analysis of the time evolution of the wave packet. The calculated sigma's are in reasonable agreement with the recent experiment in the 190-228 nm region, and the isotope shifts of the peaks for (33)S (16)O(2) and (34)S (16)O(2) relative to the corresponding peaks for (32)S (16)O(2) are in good agreement with the observed data. Relative to the sigma of (32)S (16)O(2), isotopic substitution shows a significant increment for those of (34)S (16)O(2) and (36)S (16)O(2) in the 190-228 nm region. This trend is consistent with the observed data.

Driving force of metallo (Mg–H and Mg–Cl)-ene reaction mechanisms

The potential-energy surfaces of the metallo-ene reactions of allyl-MgH and allyl-MgCl with ethylene were studied using ab initio molecular-orbital (MO) methods. The concerted path and the stepwise path of the metallo-ene reactions of allyl-MgH and allyl-MgCl with ethylene were identified and it was determined that the energy barriers on concerted paths of the metallo-ene reactions of allyl-MgH and allyl-MgCl with ethylene are lower than those on the stepwise paths. Furthermore, the concerted path of the metallo-ene reaction of allyl-MgCl with ethylene is more favorable than that of the allyl-MgH reaction system. The reaction mechanisms were analyzed using a CiLC method on the basis of CASSCF MOs. The driving force for the concerted path reactions arises from the migration process of the metal. The difference between the reactivity of allyl-MgH and allyl-MgCl can be explained with the reaction mechanism on the basis of the driving force.

Theoretical Studies on the Structures and the Aromaticity for Condensed Cyclobutadienoids Series: The Combination of Kekulé Structures

The structures and aromaticity of a series of condensed cyclobutadienoids were investigated by ab initio molecular orbital and density functional methods. A boat-type structure was found to be the most stable for all cyclobutadienoids except butalene, and the structures could also be predicted from a simple combination of asymmetric Kekulé structures. There were found to be three types of stable structure for cyclobutadienoids (C(2n)H(4)). In the case of 2n = 6m (m = 1, 2, ...), the structure consists of a succession of six-membered pi-resonance ring units, while for 2n-4 = 6m, the structure is an assembly of six-membered pi-resonance ring units with two "double-bonds" in the center or at the ends of the structure. In all other cases, the structures are of symmetric Kekule type. The aromaticity for each ring was obtained on the basis of the index of deviation from aromaticity. Although all compounds examined here (except for butalene) showed anti- or nonaromatic nature in the whole molecule, the six-membered ring units in some molecules had an aromatic nature similar to that of butalene.

Ab initio study of catalyzed and uncatalyzed amide bond formation as a model for peptide bond formation: Ammonia-formic acid and ammonia-glycine reactions

As a model reaction for peptide bond formation, the SN2 reactions between formic acid and ammonia (1) and between glycine and ammonia (2) have been studied with and without amine catalysis: using ab initio molecular orbital methods. For the simpler system (1) a number of basis sets up to 6-31G** and estimates of correlation energy by Moller-Plesset perturbation theory up to the second (MP2) and the fourth (MP4) order were used for the catalyzed and uncatalyzed reactions, respectively. For the more complex system (2) Hartree-Fock calculations using 3-21G and 6-31G basis sets were made. For these systems two reaction mechanisms have been examined: a two-step and a concerted mechanism. The stationary points of each reaction, including intermediates and transition states, have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of the reaction. For both systems the calculations demonstrate that a second ammonia molecule catalyzes amide bond formation, and that the two-step mechanism is more favorable than the concerted one for the catalyzed reaction, while for the uncatalyzed reaction both mechanisms are competitive. Correlation and polarization effects were found to be significant factors in stabilization and destabilization, respectively, of all transition states. Further, due to the cancellation of these two effects, the Hartee-Fock calculations using 3-21G and 6-31G basis sets were found to be qualitatively identical to the results from the highest level calculations performed here.

Theoretical studies of the interaction of H2O with small clusters of beryllium atoms

The interaction of a water molecule with a cluster of beryllium atoms [Ben … OH2, n = 1–5] has been examined by ab initio molecular orbital methods. The dependence of interaction energy and structure on the size of the cluster was investigated with a large basis set including polarization functions. The effects of electron correlation were considered by Moller-Plesset perturbation theory. A surprisingly large increase in the interaction energy from 5 kcal/mol to 23 kcal/mol occurs when the cluster size reaches three atoms with a decrease in the Be-O distance from 1.71 to 1.64 A. The dissociation energy shows no further large changes when the cluster size is increased to four and five atoms. The H2O is found to prefer corner binding sites significantly over edge or face sites on the clusters. The nature of the bonding between H2O and the Be clusters is discussed.

Simulated ab initio molecular orbital methods for polymers

The simulated ab initio molecular orbital method for polymers is described and analyzed in detail. It is shown that the approximations inherent in the method have their counterpart in the fully ab initio technique. The model systems of (BeH2)n and (CH2)n are studied in detail using several differently sized pattern molecules as data. The method is extended to the use of double-zeta basis sets for the first time. Results appear to be as accurate as ab initio results at considerably greater economy.

Computational Study of Excited-State Intramolecular-Proton-Transfer of o-Hydroxybenzaldehyde and Its Derivatives

Abstract The excited-state intramolecular-proton-transfer of o-hydroxybenzaldehyde and its derivatives (o-formyl-substituted phenols) was studied by means of an ab initio molecular-orbital method. The computational results are consistent with the experimental fluorescence quantum yield and support the nodal-plane model. The energy difference between the ground state and the lowest excited 1(π,π*) state decreases as the electron-withdrawing property of a substituent bonded to the carbonyl carbon of o-hydroxybenzaldehyde becomes stronger. However, the substituent effect does not largely distort the potential energy surface of o-formyl-substituted phenols.

Prototropic and metallotropic migration of isolobal fragments on indol rings. Theoretical study and NBO analysis

Molecular structures, energies, NBO analysis and sigmatropic behaviour of 1-Indenyl(dihydro)borane (1) and 1-Indenyl-threecarbonylcobalt(I) (2) were investigated using DFT and ab initio molecular orbital methods. In these compounds BH2 and Co(CO)3 fragments areisolobal. The Results of calculations using B3LYP, HF and MP2methods [Basis set 6-311+G**] showed that -BH2 and -Co(CO)3 had similar behaviour in sigmatropic shifts. Prototropic shifts in compounds 1 and 2 have similar mechanisms too. Results showed that metallotrotropic shift is faster than Prototrpic shift in compounds 1 and 2. The activation energies (Ea) of Prototropic shift in compounds 1 and 2 are 18.83 and 17.38 kcal.mol-1. These energies are higher than -BH2 shifts in compound 1 (10.11 kcal.mol-1) or migration of -Co(CO)3 fragment in compound 2 (12.39 kcal.mol-1). Lower amount of activation energy in borotropic shift and cobalt`s fragment shift show that rotation of boron and cobalt on the indol ring can happen in the ambient temperature. Calculation results revealed that migration of proton and Co(CO)3 was carried out via suprafacial[1,2]-sigmatropic mechanism while -BH2 shift took place via antrafacial [1,3]-rearangment.

Diels-Alder Reaction of 2-Pyridones Having an Acyl or a Sulfonyl Group on Nitrogen

Diels-Alder (DA) reaction of 5-methoxycarbonyl-2-pyridone, which has an electron-withdrawing acyl group at nitrogen, with 1,3-diene afforded 2-quinolone derivatives in modest yields. Further, DA reaction of 5,4-dimethoxycarbonyl-1-sulfonyl-2-pyridone gave 2-quinolone and 1-isoquinolone (1:1). DA reaction of 2-sulfonyl-l-isoquinolone afforded a functionalized phenanthridone. The site-selectivity was well correlated with the corresponding activation energies calculated using an ab initio molecular orbital method.

Formation and localization of a solvated electron in ground and low-lying excited states of Li(NH3)n and Li(H2O)n clusters: a comparison with Na(NH3)n and Na(H2O)n

A theoretical study of the ground and low-lying excited states of Li(NH(3))(n) and Li(H(2)O)(n) (n = 1-8) clusters is presented. Their structures, binding energies, vertical ionization energies and vertical transition energies were calculated using ab initio molecular orbital methods at correlated levels. Compared with Na(NH(3))(n) and Na(H(2)O)(n), the incremental binding energies and the spectroscopic energies are found to be almost metal-independent, but solvent-dependent after first-shell closure in both M(NH(3))(n) and M(H(2)O)(n) (M = Li and Na) clusters(.) Autoionization of the alkali atoms occurs via a spatial expansion of unpaired electron distribution extending to outside of the first solvation-shell, irrespective of the combinations of the metal and the solvent. The localization mode of the wave function of the solvated electron was investigated in both the ground and excited states. A change from a one-center diffuse state to a two-center localized state proceeds more quickly against n in M(H(2)O)(n) than in M(NH(3))(n), which is behind the solvent-dependence of the evaluated quantities.

Theoretical Study on N Doping in Carbon Materials for Hydrogen Storage

AbstractInteraction between nitrogen-substituted graphene-like compounds and hydrogen was investigated using ab initio molecular orbital method in the aspect of hydrogen storage. We adopted coronene as a model compound for fragmented graphene-like carbon materials and compared the interaction between hydrogen and pure or N-substituted coronenes by changing nitrogen positions. Among the assumed 19 N-substituted models, polarozabilities and HOMO–LUMO gaps were compared to evaluate physisorption and chemisorption energies. As for chemisorption, two N-substituted models were selected and closely examined to reveal the dependence on both nitrogen-substitution and hydrogen-adsorption positions. Potential energy surfaces as a function of H–H bond length and H2–coronen distance showed that the barrier height for hydrogen chemisorption strongly depends on N-substitution positions. The chemisorbed products of N-substituted coronenes are stabilized or destabilized compared with the pure carbon case depending on the sites of N-substitution and H-adsorption. These results suggest that N-substitution at certain positions possibly improve hydrogen storage properties of graphene-like materials.