On the use of electrostatic potential derived charges in molecular mechanics force fields. The relative solvation free energy of cis- and trans-N-methyl-acetamide

We have carried out free energy perturbation calculations on the relative solvation free energy of cis- and trans-N-methyl-acetamide (NMA). Experimentally, the solvation free energy difference has been found to be near zero. Using 6-31G* ab initio electrostatic potential derived charges for both the cis and trans conformations, we calculate a solvation free energy difference of 0.1 ± 0.1 kcal/mol. Using the 6-31G* charges derived for the trans conformation for both the cis and trans models leads to a solvation free energy difference of 0.9 ± 0.1 kcal/mol, compared to the value of 2.2 kcal/mol determined for the OPLS model for trans-NMA.     

A theoretical study of the rotational isomers of nitrosomethanol by semiempirical (AM1) and ab initio methods

The conformational potential energy surface as a function of the two internal torsion angles in C-nitrosomethanol has been obtained using the semiempirical AM1 method. Optimized geometries are reported for the local minima on this surface and also for the corresponding points on the HF/6-31G, 6-31G*, and 6-31G** surfaces. All methods predict cis and trans minima which occur in degenerate pairs, each pair being connected by a transition state of C_s symmetry. The AM1 structures are found to compare well with the corresponding ab initio structures. Ab initio HF/6-31G and HF/6-31G* harmonic vibrational frequencies are reported for the cis and trans forms of nitrosomethanol. When scaled appropriately the calculated frequencies are found to compare well with experimental frequencies. The ab initio calculations predict the energy barrier for cis → trans isomerization to be between 5.8 and 6.5 kcal/mol with the trans → cis isomerization barrier lying between 2.3 and 6.5 kcal/mol. The corresponding AM1 energy barriers are around 1 kcal/mol lower in energy. The ab initio calculations predict the barrier to conversion between the two cis rotamers to be very small with the AM1 value being around 1 kcal/mol. Both AM1 and ab initio calculations predict interconversion between trans rotamers to require between 1.2 and 1.4 kcal/mol.     

Structural features of muscimol, a potent GABAA receptor agonist, crystal structure and quantum chemicalab initio calculations

Muscimol, a constituent of the mushroomAmanita muscaria, is a semirigid analogue of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). X-ray structure determinations and quantum chemicalab initio calculations (HF/6-31G^*) have been carried out on the muscimol zwitterion. The solid-state conformations of the muscimol zwitterion are calculated to be 1.6–2.2 kcal/mol higher in energy than that of the calculated minimum energy structurein vacuo. A comparison of the calculated and experimental structures indicates that the hydrogen bonding network in the solid state significantly affects the geometry of the molecular structure. This conclusion is supported by results ofab initio calculations on binary complexes between muscimol and an ammonium ion and between muscimol and a methoxide anion, simulating observed hydrogen bonding in the crystal structures.     

Quantum Chemical Model of a Lysozyme+Substrate Complex and a Cooperative Process in It

This paper presents an ab initio (RHF/6-31G** and MP2(full)6-31G**) and density functional (DFT) study of the structure and energetics of formation of an intermolecular complex which is the simplest model of an active center lysozyme with a substrate. The calculated energy of complex formation is 41.4 (RHF), 53.4 (MP2), and 52.7 kcal/mole (DFT). The proton transfer reaction is a concerted reaction having an energy barrier of 41.1 (RHF), 31.6 (MP2), and 25.3 (DFT) kcal/mole.     

Generation of ‘Bare’ FeF+ by C?F Bond Activation in the Gas Phase and Evaluation of Thermochemical Data. Short communication

The title compound FeF⁺ has been generated in a Fourier-transform ion-cyclotron-resonance mass spectrometer via C? F bond activation by reacting hexafluorobenzene with bare FeO⁺. Bracketing experiments provide a bond-dissociation energy (BDE) for FeF⁺ of 86 < BDE < 101 kcal/mol. High-level CAS-MCSCF pseudopotential ab initio calculation, including 501036 electronic configurations, predict a BDF(Fe⁺? F) of 100.9 kcal/mol.     

Ab initio Calculations of the potential energy surface of the reaction of singlet methylene with the hydrogen molecule

The potential energy surface for the insertion of singlet methylene into H₂ has been computed on theab initio SCF level as well as with inclusion of electron correlation by means of the CEPA method. The results are compared with those of previous semiempirical,ab initio SCF and CI calculations. The system is a prototype of a reaction where an allowed and a symmetry-forbidden path can compete. The electron correlation energy was found to be very different for different regions of the surface, but did not have much influence on the optimum reaction path. From the computed heat of the reaction, the heat of formation of singlet methylene was estimated to be 101.5 kcal/mol. According to the calculations the reaction does not need any activation energy.     

Theoretical Calculations of β-Lactam Antibiotics. Part VII. Influence of the solvent on the basic hydrolysis of the β-lactam ring

We used semi-empirical and ab initio calculations to investigate the nucleophilic attack of the OH^? ion on the β-lactam carbonyl group. Both allowed us to detect reaction intermediates pertaining to proton-transfer reactions rather than the studied reaction. We also used the PM3 semi-empirical method to investigate the influence of the solvent on the process. The AMSOL method predicts the occurrence of a potential barrier of 20.7 kcal/mol due to the desolvation of the OH^? ion in approaching the β-lactam carbonyl group. Using the supermolecular approach and a H₂O solvation sphere of 20 molecules around the solute, the potential barrier is lowered to 17.5 kcal/mol, which is very close to the experimental value (16.7 kcal/mol).     

Mechanisms of inversion of bond configuration at the tetrahedral boron atom in five-membered chelate cycles

Mechanisms of inversion of the bond configuration at the tetrahedral boron center in five-membered chelate cycles of the 1,3,2-oxazaborolidine and 1,3,2-oxazaborolidene molecules were studied by theab initio MP2(full)/6-31G^** method. It was shown that enantiotopomerization occurs by a dissociative mechanism with the cleavage of the B←N bond and the formation of acyclic intermediates with tricoordinate planar boron atom. The calculated energy barriers to inversion of tetrahedral bond configurations at boron centers in the two chelate complexes are equal to 13.1 and 15.4 kcal mol⁻¹, respectively. In contrast to 1,3,2-oxazaborolidine, internal rotation about the B−O bond in its unsaturated analog makes an appreciable contribution to the reaction coordinate. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 250–255 February, 1999.     

Catalytic mechanism of class A beta-lactamase. I. The role of Glu166 and Serl30 in the deacylation reaction

The tetrahedral intermediate formation process, which is the first step in the deacylation reaction by class A beta-lactamase, was investigated by the ab initio molecular orbital method. In this study, benzyl penicillin was used as the substrate. From the results of our molecular dynamics study of the structure of beta-lactam antibiotics-beta-lactamase complex, the substrate, Ser70, Lys73, Ser130, Glu166 and a water molecule for the deacylation reaction were considered for construction of a model for calculation. The calculation results indicated that Glu166 plays a role in holding a water molecule, which is necessary for the deacylation reaction, and that the hydrogen bond network among Lys73Nzeta, Ser130Ogamma, and the carboxyl group of the beta-lactam antibiotics was formed by the uptake of beta-lactam antibiotics by beta-lactamase. The activation energy for this reaction was 33.3 kcal/mol, and it is very likely that the reaction occurred at body temperature. Subsequent calculation results obtained by using the model excluding Ser130 and the carboxyl group of the substrate indicated that the activation energy for this reaction was 40.8 kcal/mol, which is 7.5 kcal/mol higher than that of the previous reaction. It was found that the hydrogen bond network plays an important role in decreasing the activation energy for the tetrahedral intermediate formation reaction. Lys73Nzeta, which is located at the edge of the hydrogen bond network, played a role in forming a hydrogen bond with Glu166Oepsilon in order to help the deacylation reaction. The role of amino acid residues around the active site of class A beta-lactamase was also discussed.     

Ab initioMO calculations on the acidities of water and methanol,and hydrogen bond energies of the conjugate ions with a water molecule

The acidities, deprotonation energies, of water and methanol were calculated by the use of the ab initio self-consistent-field (SCF ) molecular orbital (MO ) method with electron correlation computed by the thirdorder Møller–Plesset perturbation method and configuration interaction with double excitations. Zero-point vibrational energy correction translational energy change, and the PV work term were included to evaluate the accurate acidities. The calculated acidity difference including these corrections was 7 kcal/mol, which is somewhat smaller than the experimental ones (9.5–12.5 kcal/mol) recently determined. The hydrogen bond energies of the conjugate ions (OH^? and CH₃O^?) with a water molecule were calculated to be 2.3 kcal/mol near the Hartree–Fock limit; this energy only amounts to 25% of the (total) hydration energy difference between the two negative ions. The aqueous solvation effect on the acidity scale was discussed.     

The thioketone–enethiol tautomerism of aliphatic thiocarbonyls: An ab initio study

Approximate minimum energy reaction paths have been calculated for two thioketone–enethiol tautomeric systems using an ab initio SCF–MO method. The calculations indicate nearly equal stabil ties of the isolated tautomers in both systems and an energy barrier of ca. 85 kcal/mol for their interconversion. This barrier is expected to be significantly lower in solution as a result of solvent–solute interactions.     

Computation of the Electronic and Spectroscopic Properties of Carbohydrates Using Novel Density Functional and Vibrational Self-Consistent Field Methods

ABSTRACT

A novel density functional method is presented for the calculation of electronic and thermodynamical properties of oligosaccharides. This method, termed K2-BVWN, offers two advantages; it scales as N ³, where N is the number of basis functions, and there are only two adjustable parameters. The current density functional method is tested in terms of reproducing high level gas phase ab initio calculations in eleven low energy conformers of D-glucopyranose including exo-anomeric and different hydroxymethyl orientations (G ^?, G ⁺, and T). The K2-BVWN method is also tested in terms of reproducing the spectroscopic features of D-glucopyranose and D-mannopyranose (α/β) as compared with both a vibrational self-consistent field calculation (VSCF) as well as experimental infrared spectroscopy. The VSCF calculations offer the advantage that it is possible to include higher order mode coupling and anharmonic effects directly into the calculation of the vibrational frequencies. In general, the K2-BVWN method reproduces the ab initio energetic trends of the different conformers of D-glucose. While the absolute energies are not the same between the ab initio and the K2-BVWN method, both methods do predict a preference for the α-anomer in the gas phase (0.4 kcal/mol ab initio, 0.0 – 0.5 kcal/mol K2-BVWN). The K2-BVWN method was able to reproduce the experimental and VSCF calculated spectrum of both D-glucopyranose and D-mannopyranose in the frequency range between 1500 – 800 cm^?1. Because the current density functional method is both relatively quick and accurate, it represents a significant advancement in the development of oligosaccharide force fields.     

MO-Studies of enzyme reaction mechanisms. I. Model molecular orbital study of the cleavage of peptides by carboxypeptidase A

Ab initio and semiempiridal (AM1) molecular orbital theory has been used to model the cleavage of formamide at the active site of carboxypeptidase A. The model active site consists of a zinc dication coordinated to two imidazoles, an acetate, a water with a hydrogen-bonded formate, and a formamide molecule as model substrate. AM1 has been compared with ab initio theory for the coordination of water and formamide to Zn⁺⁺ and found to give excellent energetic results. The course of the amide cleavage was therefore calculated with AM1. The first step of the reaction is the dissociation of the zinc-coordinated water to give an active ZnOH⁺ species. The remote formate acts as proton acceptor. This process has an activation energy of only 4.6 kcal mol^?1. The next and rate-determining step is the concerted addition of the ZnOH⁺ moiety to the formamide C?O bond. The Zn? O distance in the transition state is more than 3 Å. In four further steps, the amide nitrogen is protonated and the C? N bond cleaved. The net activation energy for the entire process is 15.5 kcal mol^?1 relative to the active site model and 19.6 kcal mol^?1 relative to the most stable point on the calculated reaction profile.     

Zur quantenchemischen Behandlung von Kation-Amid-Solvatkomplexen

A comparison ofab initio calculations employing different basis sets with corresponding CNDO/2 results for the Li⁺/HCONH₂ complex shows that these methods lead to completely different energy surfaces for this system. Reduction of the basis set, even to the minimal size, does not bring about serious changes in the results of theab initio calculations, whereas in the semiempirical treatment some methodical errors seem to occur. When using however, theab initio minimum geometry the CNDO/2 calculations also give a qualitatively correct picture for the influence of the cation on the amide modecule.     

An ab initio investigation into the SN2 reaction: Frontside attack versus backside attack in the reaction of F− with CH3F

The energy hypersurface for the attack of fluoride ion on methyl fluoride has been explored with ab initio LCAO-SCF calculations at a split-valence basis set level. Transition states for frontside and backside attack have been located. In addition to transition states, two possible F^–-CH₃F clusters have been identified. The transition state for the substitution of fluoride with retention of configuration is found to be 56 kcal/mol higher than the transition state for inversion of configuration. The transition state for hydride displacement with inversion is 62 kcal/mol above the transition state for fluoride substitution with inversion.     

Thecis-trans energy difference in bi-1-cyclopro-pen-1-yl and related compounds

Thecis-trans energy difference of bi-1-cyclopropen-1-yl and the fluorosubstituted derivatives are studied byab initio methods in order to establish the stability of the cis andtrans diene isomers.The results of theab initio method STO-3G points toward thetrans bi-1-cyclopropen-1-yl as the most stable isomer (0.2kcal/mol). The energy of the transition state is about 2.5 kcal/mol above that of thetrans isomer. The electronic transitions of the isomers are also reported.Senior Fullbright-Hays Scholar to Uruguay.     

Regioselectivity in cycloaddition reaction between phosphaacetylene and diazomethane: An ab initio study

The [3 + 2] cycloaddition reaction of phosphaacetylene with diazomethane was investigated by means of high level ab initio calculations. It was deduced that the aromatic diazaphosphole is formed via a nonaromatic intermediate. The regiospecificity of the reaction is thus determined by the energy difference between the two transition states that lead to the two possible regioisomeric intermediates. Of the transition states in the concerted pathways, the one leading to the regioisomer with two PC bonds ( 3 ) was found to be more stable at all the levels of theory investigated, including coupled-cluster singles doubles (CCSD)(T)/6-311 + G^*//Møller-Plessett(MP)2/6-311 + G^* (+ basis set superposition, BSSE, correction). The energy difference between the two transition states, however, is always less than 2 kcal/mol. When the free energies in the two reactions are calculated by use of the harmonic frequencies, the energy separation between the two transition structures remains practically unchanged. The free energy of activation ΔG^† was 21 kcal/mol at the CCSD(T)/6-311 + G^* level of theory and use of the MP2/6-31 + G^* frequencies. At the MP2 level, a rather stable complex is obtained in the initial phase of the reaction. However, the stability of the complexes decreases at the CCSD(T) level, and application of the BSSE correction results in unstable complexes. © 1997 by John Wiley & Sons, Inc.     

A molecular mechanics model for imatinib and imatinib:kinase binding

Imatinib is an important anticancer drug, which binds specifically to the Abl kinase and blocks its signalling activity. To model imatinib:protein interactions, we have developed a molecular mechanics force field for imatinib and four close analogues, which is consistent with the CHARMM force field for proteins and nucleic acids. Atomic charges and Lennard‐Jones parameters were derived from a supermolecule ab initio approach. We considered the ab initio energies and geometries of a probe water molecule interacting with imatinib fragments at 32 different positions. We considered both a neutral and a protonated imatinib. The final RMS deviation between the ab initio and force field energies, averaged over both forms, was 0.2 kcal/mol. The model also reproduces the ab initio geometry and flexibility of imatinib. To apply the force field to imatinib:Abl simulations, it is also necessary to determine the most likely imatinib protonation state when it binds to Abl. This was done using molecular dynamics free energy simulations, where imatinib is reversibly protonated during a series of MD simulations, both in solution and in complex with Abl. The simulations indicate that imatinib binds to Abl in its protonated, positively‐charged form. To help test the force field and the protonation prediction, we did MD free energy simulations that compare the Abl binding affinities of two imatinib analogs, obtaining good agreement with experiment. Finally, two new imatinib variants were considered, one of which is predicted to have improved Abl binding. This variant could be of interest as a potential drug. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010     

OPLS all-atom force field for carbohydrates

The OPLS all-atom (AA) force field for organic and biomolecular systems has been expanded to include carbohydrates. Starting with reported nonbonded parameters of alcohols, ethers, and diols, torsional parameters were fit to reproduce results from ab initio calculations on the hexopyranoses, α,β-d -glucopyranose, α,β-d -mannopyranose, α,β-d -galactopyranose, methyl α,β-d -glucopyranoside, and methyl α,β-d -mannopyranoside. In all, geometry optimizations were carried out for 144 conformers at the restricted Hartree–Fock (RHF)/6–31G* level. For the conformers with a relative energy within 3 kcal/mol of the global minima, the effects of electron correlation and basis-set extension were considered by performing single-point calculations with density functional theory at the B3LYP/6–311+G** level. The torsional parameters for the OPLS-AA force field were parameterized to reproduce the energies and structures of these 44 conformers. The resultant force field reproduces the ab initio calculated energies with an average unsigned error of 0.41 kcal/mol. The α/β ratios as well as the relative energies between the isomeric hexopyranoses are in good accord with the ab initio results. The predictive abilities of the force field were also tested against RHF/6–31G* results for d -allopyranose with excellent success; a surprising discovery is that the lowest energy conformer of d -allopyranose is a β anomer. © 1997 John Wiley & Sons, Inc. J Comput Chem 18 : 1955–1970, 1997     

Intramolecular nucleophilicS N 2 substitution at the tetrahedral carbon atom: Anab initio study

Pentacoordination of carbon atom in bicyclic organic compounds of the pentalene type was studied by theab initio RHF/6-31G^** and MP2(full)/6-31G^** methods. It was shown that intramolecularS _N 2 reactions with energy barriers within the energy scale of NMR spectroscopy can occur in systems in which a linear orientation of the attacking and leaving groups is realized. The barrier to the intramolecular nucleophilic substitution reaction in 2,3-dihydro-3-formylmethylenefuran is 36.9 (RHF) and 27.7 kcal mol⁻¹ (MP2) and decreases to 16.4 and 19.4 kcal mol⁻¹, respectively, in the case of diprotonation at the O atoms in this system. For model pentalene type compounds containing electron-deficient B atoms in the ring, theab initio calculations predict a further decrease in the barrier height (down to less than 10 kcal mol⁻¹). Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 7, pp. 1246–1256, July, 1999.