Extension of the PDDG/PM3 and PDDG/MNDO semiempirical molecular orbital methods to the halogens

The new semiempirical methods, PDDG/PM3 and PDDG/MNDO, have been parameterized for halogens. For comparison, the original MNDO and PM3 were also reoptimized for the halogens using the same training set; these modified methods are referred to as MNDO' and PM3'. For 442 halogen-containing molecules, the smallest mean absolute error (MAE) in heats of formation is obtained with PDDG/PM3 (5.6 kcal/mol), followed by PM3' (6.1 kcal/mol), PDDG/MNDO (6.6 kcal/mol), PM3 (8.1 kcal/mol), MNDO' (8.5 kcal/mol), AM1 (11.1 kcal/mol), and MNDO (14.0 kcal/mol). For normal-valent halogen-containing molecules, the PDDG methods also provide improved heats of formation over MNDO/d. Hypervalent compounds were not included in the training set and improvements over the standard NDDO methods with sp basis sets were not obtained. For small haloalkanes, the PDDG methods yield more accurate heats of formation than are obtained from density functional theory (DFT) with the B3LYP and B3PW91 functionals using large basis sets. PDDG/PM3 and PM3' also give improved binding energies over the standard NDDO methods for complexes involving halide anions, and they are competitive with B3LYP/6-311++G(d,p) results including thermal corrections. Among the semiempirical methods studied, PDDG/PM3 also generates the best agreement with high-level ab initio G2 and CCSD(T) intrinsic activation energies for S(N)2 reactions involving methyl halides and halide anions. Finally, the MAEs in ionization potentials, dipole moments, and molecular geometries show that the parameter sets for the PDDG and reoptimized NDDO methods reduce the MAEs in heats of formation without compromising the other important QM observables.     

Improving description of hydrogen bonds at the semiempirical level: water–water interactions as test case

Hydrogen bonding is not well described by available semiempirical theories. This is an important restriction because hydrogen bonds represent a key feature in many chemical and biochemical processes, besides being responsible for the singular properties of water. In this study, we describe a possible solution to this problem. The basic idea is to replace the nonphysical gaussian correction functions (GCF) appearing in the core–core repulsion terms of most MNDO‐based semiempirical methods by a simple function exhibiting the correct physical behavior in the whole range of intermolecular separation distances. The parameterized interaction function (PIF) is the sum of atom‐pair contributions, each one having five adjustable parameters. In this work, the approach is used to study water–water interactions. The parameters are optimized to reproduce a reference ab initio intermolecular energy surface for the water–water dimer obtained at the MP2/aug‐cc‐pVQZ level. OO, OH, and HH parameters are reported for the PM3 method. The results of PM3‐PIF calculations remarkably improve qualitatively and quantitatively those obtained at the standard PM3 level, both for water–dimer properties and for water clusters up to the hexamer. For example, the root‐mean‐square deviation of the PM3‐PIF interaction energies, with respect to ab initio values obtained using 700 points of the water dimer surface, is only 0.47 kcal/mol. This value is much smaller than that obtained using the standard PM3 method (4.2 kcal/mol). The PM3‐PIF water dimer energy minimum (−5.0 kcal/mol) is also much closer to ab initio data (−5.0±0.01 kcal/mol) than PM3 (−3.50 kcal/mol). The method is therefore promising for the development of new semiempirical approaches as well as for application of combined quantum mechanics and molecular mechanics techniques to investigate chemical processes in water. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 572–581, 2000     

Structure and bonding in Hartwig stretched eta(3)-hydridoborate sigma-complex of niobium(III)

Ab initio calculations at the SCF, MP2, CASSCF, and CASPT2 levels of theory with basis sets using atomic pseudopotentials have been carried out for the stretched eta(3)-hydridoborate sigma-complex of niobium, [Cl2Nb(H2B(OH)2)], in order to investigate the nature and energetics of the interaction between the transition metal and the eta(3)-hydridoborate ligand. The geometry of the complex [Cl2Nb(H2B(OH)2] and its fragments [Cl2Nb](+) and [H2B(OH)2](-) were optimized at SCF and CASSCF levels. These results are consistent with [Cl2Nb(eta(3)-H2B(OH)2)] being a Nb(III) complex in which both hydrogen and boron of the [eta(3)-H2B(OH)2](-) ligand have a bonding interaction with the niobium preserving stretching B-H bond character. The calculated values of DEF (energy required to restore the fragment from the equilibrium structure to the structure it takes in the complex) for [Cl2Nb](+) are 5.35 kcal/mol at SCF, 3.27 kcal/mol at MP2, 4.80 kcal/mol at CASSCF, and 2.82 kcal/mol at CASPT2 and for [H2B(OH)2](-) 21.13 kcal/mol at SCF, 23.85 kcal/mol at MP2, 20.69 kcal/mol at CASSCF, and 23.48 kcal/mol at CASPT2. Values of INT (stabilization energy resulting from the coordination of distorted ligand to the metal fragment) for the complex [Cl2Nb(H2B(OH)2)] are -239.35 kcal/mol at SCF, -260.00 kcal/mol at MP2, -230.76 kcal/mol at CASSCF, and -252.60 kcal/mol at CASPT2. For the complex [(eta(5)-C5H5)2Nb(H2B(OH)2)], calculations at the SCF and MP2 levels were carried out. Values of INT for [(eta(5)-C5H5)2Nb(H2B(OH)2)] are -169.93 kcal/mol at SCF and -210.62 kcal/mol at MP2. The results indicate that the bonding of the [eta(3)-H2B(OH)2](-) ligand with niobium is substantially stable. The electronic structures of [Cl2Nb(H2B(OH)2)], [(eta(5)-C5H5)2Nb(H2B(OH)2)], and its fragments are analyzed in detail as measured by Mulliken charge distributions and orbital populations.     

The first example of a nitrile hydratase model complex that reversibly binds nitriles

Nitrile hydratase (NHase) is an iron-containing metalloenzyme that converts nitriles to amides. The mechanism by which this biochemical reaction occurs is unknown. One mechanism that has been proposed involves nucleophilic attack of an Fe-bound nitrile by water (or hydroxide). Reported herein is a five-coordinate model compound ([Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+)) containing Fe(III) in an environment resembling that of NHase, which reversibly binds a variety of nitriles, alcohols, amines, and thiocyanate. XAS shows that five-coordinate [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) reacts with both methanol and acetonitrile to afford a six-coordinate solvent-bound complex. Competitive binding studies demonstrate that MeCN preferentially binds over ROH, suggesting that nitriles would be capable of displacing the H(2)O coordinated to the iron site of NHase. Thermodynamic parameters were determined for acetonitrile (DeltaH = -6.2(+/-0.2) kcal/mol, DeltaS = -29.4(+/-0.8) eu), benzonitrile (-4.2(+/-0.6) kcal/mol, DeltaS = -18(+/-3) eu), and pyridine (DeltaH = -8(+/-1) kcal/mol, DeltaS = -41(+/-6) eu) binding to [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) using variable-temperature electronic absorption spectroscopy. Ligand exchange kinetics were examined for acetonitrile, iso-propylnitrile, benzonitrile, and 4-tert-butylpyridine using (13)C NMR line-broadening analysis, at a variety of temperatures. Activation parameters for ligand exchange were determined to be DeltaH(+ +) = 7.1(+/-0.8) kcal/mol, DeltaS(+ +) = -10(+/-1) eu (acetonitrile), DeltaH(+ +) = 5.4(+/-0.6) kcal/mol, DeltaS(+ +) = -17(+/-2) eu (iso-propionitrile), DeltaH(+ +) = 4.9(+/-0.8) kcal/mol, DeltaS(+ +) = -20(+/-3) eu (benzonitrile), and DeltaH(+ +) = 4.7(+/-1.4) kcal/mol DeltaS(+ +) = -18(+/-2) eu (4-tert-butylpyridine). The thermodynamic parameters for pyridine binding to a related complex, [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) (DeltaH = -5.9(+/-0.8) kcal/mol, DeltaS = -24(+/-3) eu), are also reported, as well as kinetic parameters for 4-tert-butylpyridine exchange (DeltaH(+ +) = 3.1(+/-0.8) kcal/mol, DeltaS(+ +) = -25(+/-3) eu). These data show for the first time that, when it is contained in a ligand environment similar to that of NHase, Fe(III) is capable of forming a stable complex with nitriles. Also, the rates of ligand exchange demonstrate that low-spin Fe(III) in this ligand environment is more labile than expected. Furthermore, comparison of [Fe(III)(S(2)(Me2)N(3)(Et,Pr))](+) and [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))](+) demonstrates how minor distortions induced by ligand constraints can dramatically alter the reactivity of a metal complex.     

PDDG/PM3 and PDDG/MNDO: improved semiempirical methods

Two new semiempirical methods employing a Pairwise Distance Directed Gaussian modification have been developed: PDDG/PM3 and PDDG/MNDO; they are easily implemented in existing software, and yield heats of formation for compounds containing C, H, N, and O atoms with significantly improved accuracy over the standard NDDO schemes, PM5, PM3, AM1, and MNDO. The PDDG/PM3 results for heats of formation also show substantial improvement over density functional theory with large basis sets. The PDDG modifications consist of a single function, which is added to the existing pairwise core repulsion functions within PM3 and MNDO, a reparameterized semiempirical parameter set, and modified computation of the energy of formation of a gaseous atom. The PDDG addition introduces functional group information via pairwise atomic interactions using only atom-based parameters. For 622 diverse molecules containing C, H, N, and O atoms, mean absolute errors in calculated heats of formation are reduced from 4.4 to 3.2 kcal/mol and from 8.4 to 5.2 kcal/mol using the PDDG modified versions of PM3 and MNDO over the standard versions, respectively. Several specific problems are overcome, including the relative stability of hydrocarbon isomers, and energetics of small rings and molecules containing multiple heteroatoms. The internal consistency of PDDG energies is also significantly improved, enabling more reliable analysis of isomerization energies and trends across series of molecules; PDDG isomerization energies show significant improvement over B3LYP/6-31G* results. Comparison of heats of formation, ionization potentials, dipole moments, isomer, and conformer energetics, intermolecular interaction energies, activation energies, and molecular geometries from the PDDG techniques is made to experimental data and values from other semiempirical and ab initio methods.     

Comparison of SCC-DFTB and NDDO-based semiempirical molecular orbital methods for organic molecules

Extensive testing of the SCC-DFTB method has been performed, permitting direct comparison to data available for NDDO-based semiempirical methods. For 34 diverse isomerizations of neutral molecules containing the elements C, H, N, and O, the mean absolute errors (MAE) for the enthalpy changes are 2.7, 3.2, 5.0, 5.1, and 7.2 kcal/mol from PDDG/PM3, B3LYP/6-31G(d), PM3, SCC-DFTB, and AM1, respectively. A more comprehensive test was then performed by computing heats of formation for 622 neutral, closed-shell H, C, N, and O-containing molecules; the MAE of 5.8 kcal/mol for SCC-DFTB is intermediate between AM1 (6.8 kcal/mol) and PM3 (4.4 kcal/mol) and significantly higher than for PDDG/PM3 (3.2 kcal/mol). Similarly, SCC-DFTB is found to be less accurate for heats of formation of ions and radicals; however, it is more accurate for conformational energetics and intermolecular interaction energies, though none of the methods perform well for hydrogen bonds with strengths under ca. 7 kcal/mol. SCC-DFTB and the NDDO methods all reproduce MP2/cc-pVTZ molecular geometries with average errors for bond lengths, bond angles, and dihedral angles of only ca. 0.01 A, 1.5 degrees , and 3 degrees . Testing was also carried out for sulfur containing molecules; SCC-DFTB currently yields much less accurate heats of formation in this case than the NDDO-based methods due to the over-stabilization of molecules containing an SO bond.     

Dynamical intramolecular metal-to-metal ligand exchange of phosphine and thioether ligands in derivatives PtRu5(CO)16(mu6-C)

The complexes PtRu(5)(CO)(15)(PMe(2)Ph)(mu(6)-C) (2), PtRu(5)(CO)(14)(PMe(2)Ph)(2)(mu(6)-C) (3), PtRu(5)(CO)(15)(PMe(3))(mu(6)-C) (4), PtRu(5)(CO)(14)(PMe(3))(2)(mu(6)-C) (5), and PtRu(5)(CO)(15)(Me(2)S)(mu(6)-C) (6) were obtained from the reactions of PtRu(5)(CO)(16)(mu(6)-C) (1) with the appropriate ligand. As determined by NMR spectroscopy, all the new complexes exist in solution as a mixture of isomers. Compounds 2, 3, and 6 were characterized crystallographically. In all three compounds, the six metal atoms are arranged in an octahedral geometry, with a carbido carbon atom in the center. The PMe(2)Ph and Me(2)S ligands are coordinated to the Pt atom in 2 and 6, respectively. In 3, the two PMe(2)Ph ligands are coordinated to Ru atoms. In solution, all the new compounds undergo dynamical intramolecular isomerization by shifting the PMe(2)Ph or Me(2)S ligand back and forth between the Pt and Ru atoms. For compound 2, DeltaH++ = 15.1(3) kcal/mol, DeltaS++ = -7.7(9) cal/(mol.K), and DeltaG(298) = 17.4(6) kcal/mol for the transformation of the major isomer to the minor isomer; for compound 4, DeltaH++ = 14.0(1) kcal/mol, DeltaS++ = -10.7(4) cal/(mol.K), and DeltaG(298) = 17.2(2) kcal/mol for the transformation of the major isomer to the minor isomer; for compound 6, DeltaH++ = 18(1) kcal/mol, DeltaS++ = 21(5) cal/(mol.K) and DeltaG(298) = 12(2) kcal/mol. The shifts of the Me(2)S ligand in 6 are significantly more facile than the shifts for the phosphine ligand in compounds 2-5. This is attributed to a more stable ligand-bridged intermediate for the isomerizations of 6 than that for compounds 2-5. The intermediate for the isomerization of 6 involves a bridging Me(2)S ligand that can use two lone pairs of electrons for coordination to the metal atoms, whereas a tertiary phosphine ligand can use only one lone pair of electrons for bridging coordination.     

Zinc-homocysteine binding in cobalamin-dependent methionine synthase and its role in the substrate activation: DFT, ONIOM, and QM/MM molecular dynamics studies

Cobalamin-dependent methionine synthase (MetH) is an important metalloenzyme responsible for the biosynthesis of methionine. It catalyzes methyl transfer from N(5)-methyl-tetrahydrofolate to homocysteine (Hcy) by using a zinc ion to activate the Hcy substrate. Density functional theory (B3LYP) calculations on the active-site model in gas phase and in a polarized continuum model were performed to study the Zn coordination changes from the substrate-unbound state to the substrate-bound state. The protein effect on the Zn(2+) coordination exchange was further investigated by ONIOM (B3LYP:AMBER)-ME and EE calculations. The Zn(2+)-coordination exchange is found to be highly unfavorable in the gas phase with a high barrier and endothermicity. In the water solution, the reaction becomes exothermic and the reaction barrier is drastically decreased to about 10.0 kcal/mol. A considerable protein effect on the coordination exchange was also found; the reaction is even more exothermic and occurs without barrier. The enzyme was suggested to constrain the zinc coordination sphere in the reactant state (Hcy-unbound state) more than that in the product state (Hcy-bound state), which promotes ligation of the Hcy substrate. Molecular dynamics simulations using molecular mechanics (MM) and PM3/MM potentials suggest a correlation between the flexibility of the Zn(2+)-binding site and regulation of the enzyme function. Directed in silico mutations of selected residues in the active site were also performed. Our studies support a dissociative mechanism starting with the Zn-O(Asn234) bond breaking followed by the Zn-S((Hcy)) bond formation; the proposed associative mechanism for the Zn(2+)-coordination exchange is not supported.     

Density functional theory investigation of the remarkable reactivity of geminal dizinc carbenoids (RZn)(2)CHI (R = Et or I) as cyclopropanation reagents with olefins compared to mono zinc carbenoids RZnCHI(2), EtCHIZnR (R = Et or I)

Density functional theory calculations for the cyclopropanation reactions of several mono zinc carbenoids and their corresponding gem-dizinc carbenoids with ethylene are reported. The mono zinc carbenoids react with ethylene via an asynchronous attack on one CH2 group of ethylene with a relatively high barrier to reaction in the 20-25 kcal/mol range similar to other Simmons-Smith type carbenoids previously studied. In contrast, the gem-dizinc carbenoids react with ethylene via a synchronous attack on both CH2 groups of ethylene and substantially lower barriers to reaction (about 15 kcal/mol) compared to their corresponding mono zinc carbenoid. Both mono zinc and gem-dizinc carbenoid reactions can be accelerated by the addition of ZnI2 groups as a Lewis acid, and this lowers the barrier by another 1.0-5.1 kcal/mol and 0.0-5.5 kcal/mol, respectively, for addition of one ZnI2 group. Our results indicate that gem-dizinc carbenoids react with C=C bonds with significantly lower barriers to reaction and in a noticeably different manner than Simmons-Smith type mono zinc carbenoids. The three gem-dizinc carbenoids have a substantially larger positive charge distribution than those in the mono zinc carbenoids and, hence, a stronger electrophilic character for the gem-dizinc carbenoids.     

Low-energy tautomers and conformers of neutral and protonated arginine.

The relative stabilities of zwitterionic and canonical forms of neutral arginine and of its protonated derivative were studied by using ab initio electronic structure methods. Trial structures were first identified at the PM3 level of theory with use of a genetic algorithm to systematically vary geometrical parameters. Further geometry optimizations of these structures were performed at the MP2 and B3LYP levels of theory with basis sets of the 6-31++G** quality. The final energies were determined at the CCSD/6-31++G** level and corrected for thermal effects determined at the B3LYP level. Two new nonzwitterionic structures of the neutral were identified, and one of them is the lowest energy structure found so far. The five lowest energy structures of neutral arginine are all nonzwitterionic in nature and are clustered within a narrow energy range of 2.3 kcal/mol. The lowest energy zwitterion structure is less stable than the lowest nonzwitterion structure by 4.0 kcal/mol. For no level of theory is a zwitterion structure suggested to be the global minimum. The calculated proton affinity of 256.3 kcal/mol and gas-phase basicity of 247.8 kcal/mol of arginine are in reasonable agreement with the measured values of 251.2 and 240.6 kcal/mol, respectively. The calculated vibrational characteristics of the low-energy structures of neutral arginine provide an alternative interpretation of the IR-CRLAS spectrum (Chapo et al. J. Am. Chem. Soc. 1998, 120, 12956-12957).     

Computation of relative binding free energy for an inhibitor and its analogs binding with Erk kinase using thermodynamic integration MD simulation

In the present study, we carried out thermodynamic integration molecular dynamics simulation for a pair of analogous inhibitors binding with Erk kinase to investigate how computation performs in reproducing the relative binding free energy. The computation with BCC-AM1 charges for ligands gave ?1.1?kcal/mol, deviated from experimental value of ?2.3?kcal/mol by 1.2?kcal/mol, in good agreement with experimental result. The error of computed value was estimated to be 0.5?kcal/mol. To obtain convergence, switching vdw interaction on and off required approximately 10 times more CPU time than switching charges. Residue-based contributions and hydrogen bonding were analyzed and discussed. Furthermore, subsequent simulation using RESP charge for ligand gave ΔΔG of ?1.6?kcal/mol. The computed results are better than the result of ?5.6?kcal/mol estimated using PBSA method in a previous study. Based on these results, we further carried out computations to predict ΔΔG for five new analogs, focusing on placing polar and nonpolar functional groups at the meta site of benzene ring shown in the Fig.?1, to see if these ligands have better binding affinity than the above ligands. The computations resulted that a ligand with polar –OH group has better binding affinity than the previous examined ligand by ~2.0?kcal/mol and two other ligands have better affinity by ~1.0?kcal/mol. The predicted better inhibitors of this kind should be of interest to experimentalist for future experimental enzyme and/or cell assays.     

Mononuclear nitrogen/sulfur-ligated zinc methoxide and hydroxide complexes: investigating ligand effects on the hydrolytic stability of zinc alkoxide species

The synthesis and properties of mononuclear zinc methoxide ([(ebnpa)Zn-OCH3]ClO4) (1) and hydroxide ([(ebnpa)Zn-OH]ClO4) (2) complexes of a new mixed nitrogen/sulfur ligand (ebnpa = N-2-(ethylthio)ethyl-N,N-bis(6-neopentylamino-2-pyridylmethyl)amine) are reported. The structures of 1 and 2 were determined by X-ray diffraction. Each possesses a single zinc-coordinated anion (methoxide or hydroxide) and exhibits an overall trigonal bipyramidal geometry. Structural and spectroscopic studies indicate the presence of two hydrogen-bonding interactions involving the oxygen atom of the zinc-bound anion in each complex. Treatment of [(ebnpa)Zn-OH]ClO4 with CH3OH results in the formation of an equilibrium mixture of 1 and 2. 1H NMR spectroscopic methods were used to examine the equilibrium as a function of temperature, yielding KMe (304 K) = 0.30(8), DeltaHMe = -0.9(1) kcal/mol, and DeltaSMe = -5(1) eu. The negative enthalpy indicates that spontaneous zinc alkoxide formation from a hydroxide precursor occurs in this system at low temperature. Using the experimentally determined DeltaHMe value, we found the homolytic Zn-O bond dissociation energy (BDE) in the Zn-OCH3 unit to be approximately -14 kcal/mol relative to the Zn-O BDE in the Zn-OH unit.     

Optimization and application of lithium parameters for PM3

Lithium parameters have been optimized for Stewart's standard PM3 method. The average deviation of the heats of formation calculated for 18 reference compounds is 6.2 kcal/mol from the experimental or high-level ab initio data; the average deviation with Li/MNDO is 18.9 kcal/mol. The average error in bond lengths is also reduced by a factor of two to three. Ionization potentials and dipole moments are reproduced with comparable accuracy than Li/MNDO. However, the mean deviation for the heats of formation of both methods increases when being applied to other systems, especially to small inorgnic molecules. The applicability of the new parameter set is demonstrated further for various compounds not included in the reference set, for the calculation of the activation barriers of several lithiation reactions, as well as for the estimation of oligomerization energies of methyl lithium (including the tetramer). Li/PM3 gives reliable results even for large dimeric complexes, like [{4-(CH₃CR)C₅H₄N}Li]₂, containing TMEDA or THF as coligands and reproduces the haptotropic interaction between Li⁺ and π-systems (e.g., in benzyl lithium) as well as the relative energies and structural features of compounds with “hypervalent” atoms (e.g., in lithiated sulfones). © John Wiley & Sons, Inc.     

Ab initio and density functional theory reinvestigation of gas-phase sulfuric acid monohydrate and ammonium hydrogen sulfate

We have calculated the thermochemical parameters for the reactions H(2)SO(4) + H(2)O <--> H(2)SO(4).H(2)O and H(2)SO(4) + NH(3) <--> H(2)SO(4).NH(3) using the B3LYP and PW91 functionals, MP2 perturbation theory and four different basis sets. Different methods and basis sets yield very different results with respect to, for example, the reaction free energies. A large part, but not all, of these differences are caused by basis set superposition error (BSSE), which is on the order of 1-3 kcal mol(-1) for most method/basis set combinations used in previous studies. Complete basis set extrapolation (CBS) calculations using the cc-pV(X+d)Z and aug-cc-pV(X+d)Z basis sets (with X = D, T, Q) at the B3LYP level indicate that if BSSE errors of less than 0.2 kcal mol(-1) are desired in uncorrected calculations, basis sets of at least aug-cc-pV(T+d)Z quality should be used. The use of additional augmented basis functions is also shown to be important, as the BSSE error is significant for the nonaugmented basis sets even at the quadruple-zeta level. The effect of anharmonic corrections to the zero-point energies and thermal contributions to the free energy are shown to be around 0.4 kcal mol(-1) for the H(2)SO(4).H(2)O cluster at 298 K. Single-point CCSD(T) calculations for the H(2)SO(4).H(2)O cluster also indicate that B3LYP and MP2 calculations reproduce the CCSD(T) energies well, whereas the PW91 results are significantly overbinding. However, basis-set limit extrapolations at the CCSD(T) level indicate that the B3LYP binding energies are too low by ca. 1-2 kcal/mol. This probably explains the difference of about 2 kcal mol(-1) for the free energy of the H(2)SO(4) + H(2)O <--> H(2)SO(4).H(2)O reaction between the counterpoise-corrected B3LYP calculations with large basis sets and the diffusion-based experimental values of S. M. Ball, D. R. Hanson, F. L Eisele and P. H. McMurry (J. Phys. Chem. A. 2000, 104, 1715). Topological analysis of the electronic charge density based on the quantum theory of atoms in molecules (QTAIM) shows that different method/basis set combinations lead to qualitatively different bonding patterns for the H(2)SO(4).NH(3) cluster. Using QTAIM analysis, we have also defined a proton transfer degree parameter which may be useful in further studies.     

Probing phenylalanine/adenine pi-stacking interactions in protein complexes with explicitly correlated and CCSD(T) computations

To examine the effects of pi-stacking interactions between aromatic amino acid side chains and adenine bearing ligands in crystalline protein structures, 26 toluene/(N9-methyl)adenine model configurations have been constructed from protein/ligand crystal structures. Full geometry optimizations with the MP2 method cause the 26 crystal structures to collapse to six unique structures. The complete basis set (CBS) limit of the CCSD(T) interaction energies has been determined for all 32 structures by combining explicitly correlated MP2-R12 computations with a correction for higher-order correlation effects from CCSD(T) calculations. The CCSD(T) CBS limit interaction energies of the 26 crystal structures range from -3.19 to -6.77 kcal mol (-1) and average -5.01 kcal mol (-1). The CCSD(T) CBS limit interaction energies of the optimized complexes increase by roughly 1.5 kcal mol (-1) on average to -6.54 kcal mol (-1) (ranging from -5.93 to -7.05 kcal mol (-1)). Corrections for higher-order correlation effects are extremely important for both sets of structures and are responsible for the modest increase in the interaction energy after optimization. The MP2 method overbinds the crystal structures by 2.31 kcal mol (-1) on average compared to 4.50 kcal mol (-1) for the optimized structures.     

Application of the computationally efficient self-consistent-charge density-functional tight-binding method to magnesium-containing molecules

The geometric properties, ionization potentials, heats of formation, incremental binding energies, and protonation energies for up to 75 magnesium-containing compounds have been studied using the self-consistent-charge density-functional tight-binding method (SCC-DFTB), the complete-basis set (CBS-QB3) method, traditional B3LYP density-functional theory, and a number of modern semiempirical methods such as Austin Model 1 (AM1), modified neglect of diatomic overlap without and with inclusion of d functions (MNDO, MNDO/d), and the Parametric Method 3 (PM3) and its modification (PM5). The test set contains some widely varying chemical motifs including ionic or covalent, closed-shell or radical compounds, and many biologically relevant complexes. Geometric data are compared to experiment, if available, and otherwise to previous high-level ab initio calculations or the present B3LYP results. SCC-DFTB is found to predict bond lengths to high accuracy, with the root-mean-square (RMS) error being less than half that found for the other semiempirical methods. However, SCC-DFTB performs very poorly for absolute heats of formation, giving an RMS error of 29 kcal mol(-1), but for this property B3LYP and the other semiempirical methods also yield poor but useful results with errors of 12-22 kcal mol(-1). Nevertheless, SCC-DFTB does provide useful results for biologically relevant chemical-process energies such as protonation energies (RMS error 10 kcal mol(-1), with the range 6-19 kcal mol(-1) found for the other semiempirical methods) and ligation energies (RMS error 9 kcal mol(-1), less than the errors of 12-23 kcal mol(-1) found for the other semiempirical methods). SCC-DFTB is shown to provide a computationally expedient means of calculating properties of magnesium compounds, providing results with at most double the inaccuracy of the high-quality but dramatically more-expensive B3LYP method.     

Detailed potential of mean force studies on host–guest systems from the SAMPL6 challenge

Accurately predicting receptor–ligand binding free energies is one of the holy grails of computational chemistry with many applications in chemistry and biology. Many successes have been reported, but issues relating to sampling and force field accuracy remain significant issues affecting our ability to reliably calculate binding free energies. In order to explore these issues in more detail we have examined a series of small host–guest complexes from the SAMPL6 blind challenge, namely octa-acids (OAs)–guest complexes and Curcurbit[8]uril (CB8)–guest complexes. Specifically, potential of mean force studies using umbrella sampling combined with the weighted histogram method were carried out on both systems with both known and unknown binding affinities. We find that using standard force fields and straightforward simulation protocols we are able to obtain satisfactory results, but that simply scaling our results allows us to significantly improve our predictive ability for the unknown test sets: the overall RMSD of the binding free energy versus experiment is reduced from 5.59 to 2.36 kcal/mol; for the CB8 test system, the RMSD goes from 8.04 to 3.51 kcal/mol, while for the OAs test system, the RSMD goes from 2.89 to 0.95 kcal/mol. The scaling approach was inspired by studies on structurally related known benchmark sets: by simply scaling, the RMSD was reduced from 6.23 to 1.19 kcal/mol and from 2.96 to 0.62 kcal/mol for the CB8 benchmark system and the OA benchmark system, respectively. We find this scaling procedure to correct absolute binding affinities to be highly effective especially when working across a “congeneric” series with similar charge states. It is less successful when applied to mixed ligands with varied charges and chemical characteristics, but improvement is still realized in the present case. This approach suggests that there are large systematic errors in absolute binding free energy calculations that can be straightforwardly accounted for using a scaling procedure. Random errors are still an issue, but near chemical accuracy can be obtained using the present strategy in select cases.     

Accurate thermochemical properties for energetic materials applications. I. Heats of formation of nitrogen-containing heterocycles and energetic precursor molecules from electronic structure theory

The heats of formation of 1H-imidazole, 1H-1,2,4-trizazole, 1H-tetrazole, CH3NO2, CH3N3, CH3NH2, CH2CHNO2, HClO4, and phenol, as well as cations and anions derived from some of the molecules have been calculated using ab initio molecular orbital theory. These molecules are important as models for compounds used for energetic materials synthesis. The predicted heats of formation of the heterocycle-based compounds are in excellent agreement with available experimental values and those derived from proton affinities and deprotonation enthalpies to <1 kcal/mol. The predicted value for the tetrazolium cation differs substantially from the experimental value, likely due to uncertainty in the measurement. The heats of formation of the nitro and amino molecules, as well as phenol/phenolate, also are in good agreement with the experimental values (<1.5 kcal/mol). The heat of formation of CH3N3 is predicted to be 72.8 kcal/mol at 298 K with an estimated error bar of +/-1 kcal/mol on the basis of the agreement between the calculated and experimental values for DeltaH(f)(HN3). The heat of formation at 298 K of HClO4 is -0.4 kcal/mol, in very good agreement with the experimental value, as well as a W2 literature study. An extrapolation of the CCSD(T)/aug-cc-pV(Q,5) energies was required to obtain this agreement. This result suggests that very large basis sets (> or =aug-cc-pV5Z) may be needed to fully recover the valence correlation energy contribution in compounds containing elements with high formal oxidation states at the central atom. In addition tight d functions are needed for the geometry predictions. Douglas-Kroll-Hess (DKH) scalar relativistic corrections for HClO4 and ClO4- at the MP2 level with correlation-consistent DKH basis sets were predicted to be large, likely due to the high formal oxidation state at the Cl.     

Accurate heats of formation of the "Arduengo-type" carbene and various adducts including H2 from ab initio molecular orbital theory

The heats of formation of saturated and unsaturated diaminocarbenes (imadazol(in)-2-ylidenes) have been calculated by using high levels of ab initio electronic structure theory. The calculations were done at the coupled cluster level through noniterative triple excitations with augmented correlation consistent basis sets up through quadruple. In addition, four other corrections were applied to the frozen core atomization energies: (1) a zero point vibrational correction; (2) a core/valence correlation correction; (3) a scalar relativistic correction; (4) a first-order atomic spin-orbit correction. The value of DeltaHf( 298) for the unsaturated carbene 1 is calculated to be 56.4 kcal/mol. The value of DeltaHf( 298) for the unsaturated triplet carbene (3)1 is calculated to be 142.8 kcal/mol, giving a singlet-triplet splitting of 86.4 kcal/mol. Addition of a proton to 1 forms 3 with DeltaHf( 298)(3) = 171.6 kcal/mol with a proton affinity for 1 of 250.5 kcal/mol at 298 K. Addition of a hydrogen atom to 1 forms 4 with DeltaHf( 298)(4) = 72.7 kcal/mol and a C-H bond energy of 35.8 kcal/mol at 298 K. Addition of H- to 1 gives 5 with DeltaHf( 298)(5) = 81.2 kcal/mol and 5 is not stable with respect to loss of an electron to form 4. Addition of H2 to the carbene center forms 6 with DeltaHf( 298)(6) = 41.5 kcal/mol and a heat of hydrogenation at 298 K of -14.9 kcal/mol. The value of DeltaHf( 298) for the saturated carbene 7 (obtained by adding H2 to the C=C bond of 1) is 47.4 kcal/mol. Hydrogenation of 7 to form the fully saturated imidazolidine, 8, gives DeltaHf( 298)(8) = 14.8 kcal/mol and a heat of hydrogenation at 298 K of -32.6 kcal/mol. The estimated error bars for the calculated heats of formation are +/-1.0 kcal/mol.