Improved pseudobonds for combined ab initio quantum mechanical/molecular mechanical methods

The pseudobond approach offers a smooth connection at the quantum mechanical/molecular mechanical interface which passes through covalent bonds. It replaces the boundary atom of the environment part with a seven-valence-electron atom to form a pseudobond with the boundary atom of the active part [Y. Zhang, T. S. Lee, and W. Yang, J. Chem. Phys. 110, 46 (1999)]. In its original formulation, the seven-valence-electron boundary atom has the basis set of fluorine and a parametrized effective core potential. Up to now, only the Cps(sp3)-C(sp3) pseudobond has been successfully developed; thus in the case of proteins, it can only be used to cut the protein side chains. Here we employ a different formulation to construct this seven-valence-electron boundary atom, which has its own basis set as well as the effective core potential. We have not only further improved Cps(sp3)-C(sp3) pseudobond, but also developed Cps(sp3)-C(sp2,carbonyl) and Cps(sp3)-N(sp3) pseudobonds for the cutting of protein backbones and nucleic acid bases. The basis set and effective core potential for the seven-valence-electron boundary atom are independent of the molecular mechanical force field. Although the parametrization is performed with density functional calculations using hybrid B3LYP exchange-correlation functional, it is found that the same set of parameters is also applicable to Hartree-Fock and MP2 methods, as well as DFT calculations with other exchange-correlation functionals. Tests on a series of molecules yield very good structural, electronic, and energetic results in comparison with the corresponding full ab initio quantum mechanical calculations.     

IR spectra of N-methylacetamide in water predicted by combined quantum mechanical/molecular mechanical molecular dynamics simulations

We applied the combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulation method in assessing IR spectra of N-methylacetamide and its deuterated form in aqueous solutions. The model peptide is treated at the Austin Model 1 (AM1) level and the induced dipole effects by the solvent are incorporated in fluctuating solute dipole moments, which are calculated using partial charges from Mulliken population analyses without resorting to any available high-level ab initio dipole moment data. Fourier transform of the solute dipole autocorrelation function produces in silico IR spectra, in which the relative peak intensities and bandwidths of major amide bands are quantitatively compatible with experimental results only when both geometric and electronic polarizations of the peptide by the solvent are dealt with at the same quantum-mechanical level. We cast light on the importance of addressing dynamic charge fluctuations of the solute in calculating IR spectra by comparing classical and QM/MM MD simulation results. We propose the adjustable scaling factors for each amide mode to be directly compared with experimental data.     

Spectroscopic and quantum chemical studies on proton motion in bifurcated hydrogen-bonded systems

The infrared spectra of crystalline 1,8-bis (N,N-dimethylamino) naphthalene hydrohalides within the proton absorption range have been studied. The spectral features suggest a bifurcated interaction of the [N H N]⁺ cation with the relevant ionic species. Quantum-chemical SCF-MO-LCAO ab initio calculation of the potential energy curves for the proton motion were carried out for the model [H₃N H NH₃]⁺ H⁻ system. Preliminary calculations corroborate the experimental conclusions about the proton motion mechanism.     

A combined quantum mechanical and molecular mechanical study of the reaction mechanism and alpha-amino acidity in alanine racemase

Combined quantum mechanical/molecular mechanical simulations have been carried out to investigate the origin of the carbon acidity enhancement in the alanine racemization reaction catalyzed by alanine racemase (AlaR). The present study shows that the enhancement of carbon acidity of alpha-amino acids by the cofactor pyridoxal 5'-phosphate (PLP) with an unusual, unprotonated pyridine is mainly due to solvation effects, in contrast to the intrinsic electron-withdrawing stabilization by the pyridinium ion to form a quinonoid intermediate. Alanine racemase further lowers the alpha-proton acidity and provides an overall 14-17 kcal/mol transition-state stabilization. The second key finding of this study is that the mechanism of racemization of an alanine zwitterion in water is altered from an essentially concerted process to a stepwise reaction by formation of an external aldimine adduct with the PLP cofactor. Finally, we have used a centroid path integral method to determine the intrinsic kinetic isotope effects for the two proton abstraction reactions, which are somewhat greater than the experimental estimates.     

Finite element interpolation for combined classical/quantum mechanical molecular dynamics simulations

A method is presented to interpolate the potential energy function for a part of a system consisting of a few degrees of freedom, such as a molecule in solution. The method is based on a modified finite element (FE) interpolation scheme. The aim is to save computer time when expensive methods such as quantum-chemical calculations are used to determine the potential energy function. The expensive calculations are only carried out if the molecule explores new unknown regions of the conformation space. If the molecule resides in regions previously explored, a cheap interpolation is performed instead of an expensive calculation, using known neighboring points. We report the interpolation techniques for the energies and the forces of the molecule, the handling of the FE mesh, and an application to a simple test example in molecular dynamics (MD) simulations. Good performance of the method was obtained (especially for MD simulations with a preceding Monte Carlo mesh generation) without losing accuracy. © 1997 John Wiley & Sons, Inc. J Comput Chem 18 : 1484–1495, 1997     

Reaction path potential for complex systems derived from combined ab initio quantum mechanical and molecular mechanical calculations

Combined ab initio quantum mechanical and molecular mechanical calculations have been widely used for modeling chemical reactions in complex systems such as enzymes, with most applications being based on the determination of a minimum energy path connecting the reactant through the transition state to the product in the enzyme environment. However, statistical mechanics sampling and reaction dynamics calculations with a combined ab initio quantum mechanical (QM) and molecular mechanical (MM) potential are still not feasible because of the computational costs associated mainly with the ab initio quantum mechanical calculations for the QM subsystem. To address this issue, a reaction path potential energy surface is developed here for statistical mechanics and dynamics simulation of chemical reactions in enzymes and other complex systems. The reaction path potential follows the ideas from the reaction path Hamiltonian of Miller, Handy and Adams for gas phase chemical reactions but is designed specifically for large systems that are described with combined ab initio quantum mechanical and molecular mechanical methods. The reaction path potential is an analytical energy expression of the combined quantum mechanical and molecular mechanical potential energy along the minimum energy path. An expansion around the minimum energy path is made in both the nuclear and the electronic degrees of freedom for the QM subsystem internal energy, while the energy of the subsystem described with MM remains unchanged from that in the combined quantum mechanical and molecular mechanical expression and the electrostatic interaction between the QM and MM subsystems is described as the interaction of the MM charges with the QM charges. The QM charges are polarizable in response to the changes in both the MM and the QM degrees of freedom through a new response kernel developed in the present work. The input data for constructing the reaction path potential are energies, vibrational frequencies, and electron density response properties of the QM subsystem along the minimum energy path, all of which can be obtained from the combined quantum mechanical and molecular mechanical calculations. Once constructed, it costs much less for its evaluation. Thus, the reaction path potential provides a potential energy surface for rigorous statistical mechanics and reaction dynamics calculations of complex systems. As an example, the method is applied to the statistical mechanical calculations for the potential of mean force of the chemical reaction in triosephosphate isomerase.     

Promoting vibrations in human purine nucleoside phosphorylase. A molecular dynamics and hybrid quantum mechanical/molecular mechanical study

Crystallographic studies of human purine nucleoside phosphorylase (hPNP) with several transition-state (TS) analogues in the immucillin family showed an unusual geometric arrangement of the atoms O-5', O-4', and O(P), the nucleophilic phosphate oxygen, lying in a close three-oxygen stack. These observations were corroborated by extensive experimental kinetic isotope effect analysis. We propose that protein-facilitated dynamic modes in hPNP cause this stack, centered on the ribosyl O-4' oxygen, to squeeze together and push electrons toward the purine ring, stabilizing the oxacarbenium character of the TS. As the N-ribosidic bond is cleaved during the reaction, the pK(a) values of N-7 and O-6 increase by the electron density expelled by the oxygen-stack compression toward the purine ring. Increased electron density in the purine ring improves electrostatic interactions with nearby residues and facilitates the abstraction of a proton from a solvent proton or an unidentified general acid, making the purine a better leaving group, and accelerating catalysis. Classical and mixed quantum/classical molecular dynamics (MD) simulations of the Michaelis complex of hPNP with the substrates guanosine and phosphate were performed to assess the existence of protein-promoting vibrations (PPVs). Analogous simulations were performed for the substrates in aqueous solution. In the catalytic site, the O-5', O-4', and O(P) oxygens vibrate at frequencies of ca. 125 and 465 cm(-1), as opposed to 285 cm(-1) in the absence of hPNP. The hybrid quantum mechanical/molecular mechanical method was used to assess whether this enzymatic vibration pushing the oxygens together is coupled to the reaction coordinate, and thus has a direct positive impact on catalysis. The potential energy surface for the phosphorolysis reaction for several snapshots taken from the classical MD simulation showed substantial differences in oxygen compression. Our calculations showed the existence of PPVs coupled to the reaction coordinate, which effect electronic alterations in the active site by pushing the three oxygen centers together in proximity, and accelerate substrate turnover in the phosphorolysis reaction catalyzed by hPNP.     

Nonadiabatic transitions in chemical reactions: A quantum mechanical study

This work presents an exact quantum mechanical treatment of a reactive three-atom collinear model system incorporating nonadiabatic couplings. It was assumed that nonadiabatic transitions are induced by the vibrational motion only. The main findings are: (i) The reaction process can create conditions in which weak nonadiabatic couplings terms ( for which the Massey parameter was round 10) may cause large probabilities (～0.5) for transitions from one electronic surface to the other. In other words, the reaction process is able in certain cases to create a near resonance situation which makes the non-adiabatic transition almost independent of the magnitude of the coupling term. For this to happen the two surfaces need not be proximate, nor need they “almost” cross along a certain line (ii) In cases where the main nonadiabatic transitions take place outside the interaction region one may, at least qualitatively, decouple the reaction process from the nonadiabatic one. Thus, under the conditions specified one may first treat the reactive system on the ground state surface without including the excited interacting surface and then treat the nonadiabatic process independently.     

The catalytic activity of proline racemase: a quantum mechanical/molecular mechanical study

The enzyme proline racemase from the eukaryotic parasite Trypanosoma cruzi (responsible for endemic Chagas disease) catalyzes the reversible stereoinversion of chiral Calpha in proline. We employed a new combined quantum mechanical and molecular mechanical (QM/MM) potential to study the reaction mechanism of the enzyme. Three critical points were found: two almost isoenergetic minima (M1a and M2a), in which the enzyme is bound to L- and D-Pro, respectively, and a transition state (TSCa), unveiling a highly asynchronous concerted process. A systematic analysis was performed on the optimized geometries to point out the key role played by some residues in stabilizing the transition state.     

Solvent effect on the absorption spectra of coumarin 120 in water: A combined quantum mechanical and molecular mechanical study

The solvent effect on the absorption spectra of coumarin 120 (C120) in water was studied utilizing the combined quantum mechanical∕molecular mechanical (QM∕MM) method. In molecular dynamics (MD) simulation, a new sampling scheme was introduced to provide enough samples for both solute and solvent molecules to obtain the average physical properties of the molecules in solution. We sampled the structure of the solute and solvent molecules separately. First, we executed a QM∕MM MD simulation, where we sampled the solute molecule in solution. Next, we chose random solute structures from this simulation and performed classical MD simulation for each chosen solute structure with its geometry fixed. This new scheme allowed us to sample the solute molecule quantum mechanically and sample many solvent structures classically. Excitation energy calculations using the selected samples were carried out by the generalized multiconfigurational perturbation theory. We succeeded in constructing the absorption spectra and realizing the red shift of the absorption spectra found in polar solvents. To understand the motion of C120 in water, we carried out principal component analysis and found that the motion of the methyl group made the largest contribution and the motion of the amino group the second largest. The solvent effect on the absorption spectrum was studied by decomposing it in two components: the effect from the distortion of the solute molecule and the field effect from the solvent molecules. The solvent effect from the solvent molecules shows large contribution to the solvent shift of the peak of the absorption spectrum, while the solvent effect from the solute molecule shows no contribution. The solvent effect from the solute molecule mainly contributes to the broadening of the absorption spectrum. In the solvent effect, the variation in C-C bond length has the largest contribution on the absorption spectrum from the solute molecule. For the solvent effect on the absorption spectrum from the solvent molecules, the solvent structure around the amino group of C120 plays the key role.     

Performance assessment of semiempirical molecular orbital methods in describing halogen bonding: quantum mechanical and quantum mechanical/molecular mechanical-molecular dynamics study

The performance of semiempirical molecular-orbital methods--MNDO, MNDO-d, AM1, RM1, PM3 and PM6--in describing halogen bonding was evaluated, and the results were compared with molecular mechanical (MM) and quantum mechanical (QM) data. Three types of performance were assessed: (1) geometrical optimizations and binding energy calculations for 27 halogen-containing molecules complexed with various Lewis bases (Two of the tested methods, AM1 and RM1, gave results that agree with the QM data.); (2) charge distribution calculations for halobenzene molecules, determined by calculating the solvation free energies of the molecules relative to benzene in explicit and implicit generalized Born (GB) solvents (None of the methods gave results that agree with the experimental data.); and (3) appropriateness of the semiempirical methods in the hybrid quantum-mechanical/molecular-mechanical (QM/MM) scheme, investigated by studying the molecular inhibition of CK2 protein by eight halobenzimidazole and -benzotriazole derivatives using hybrid QM/MM molecular-dynamics (MD) simulations with the inhibitor described at the QM level by the AM1 method and the rest of the system described at the MM level. The pure MM approach with inclusion of an extra point of positive charge on the halogen atom approach gave better results than the hybrid QM/MM approach involving the AM1 method. Also, in comparison with the pure MM-GBSA (generalized Born surface area) binding energies and experimental data, the calculated QM/MM-GBSA binding energies of the inhibitors were improved by replacing the G(GB,QM/MM) solvation term with the corresponding G(GB,MM) term.     

Electrostatic molecular potentials in hydrogen-bonded systems

A study is made of the modifications of the electrostatic molecular potential brought about by hydrogen bonding both in the hydrogen-bond region itself and in the external regions of the proton-acceptor and proton-donor molecules. Systems up to four successive units in a chain of donor-acceptors are considered. The possibility of obtaining a satisfactory picture of the global potential by a simple superposition of the potentials of the individual units is evaluated.     

Simulations of liquid ammonia based on the combined quantum mechanical/molecular mechanical (QM/MM) approach

Two combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations, namely, HF/MM and B3LYP/MM, have been performed to investigate the local structure and dynamics of liquid ammonia. The most interesting region, a sphere containing a central reference molecule and all its nearest surrounding molecules (first coordination shell), was treated by the Hartree-Fock (HF) and hybrid density functional B3LYP methods, whereas the rest of the system was described by the classical pair potentials. On the basis of both HF and B3LYP methods, it is observed that the hydrogen bonding in this peculiar liquid is weak. The structure and dynamics of this liquid are suggested to be determined by the steric packing effects, rather than by the directional hydrogen bonding interactions. Compared to previous empirical as well as Car-Parrinello (CP) molecular dynamics studies, our QM/MM simulations provide detailed information that is in better agreement with experimental data.     

A quantum mechanical/molecular mechanical study on the catalysis of the pyridoxal 5'-phosphate-dependent enzyme L-serine dehydratase

The catalytic mechanism of a pyridoxal 5'-phosphate-dependent enzyme, l-serine dehydratase, has been investigated using ab initio quantum mechanical/molecular mechanical (QM/MM) methods. New insights into the chemical steps have been obtained, including the chemical role of the substrate carboxyl group in the Schiff base formation step and a proton-relaying mechanism involving the phosphate of the cofactor in the beta-hydroxyl-leaving step. The latter step is of no barrier and follows sequentially after the elimination of the alpha-proton, leading to a single but sequential alpha, beta-elimination step. The rate-limiting transition state is specifically stabilized by the enzyme environment. At this transition state, charges are localized on the substrate carboxyl group, as well as on the amino group of Lys41. Specific interactions of the enzyme environment with these groups are able to lower the activation barrier significantly. One major difficulty associated with studies of complicated enzymatic reactions using ab initio QM/MM models is the appropriate choices of reaction coordinates. In this study, we have made use of efficient semiempirical models and pathway optimization techniques to overcome this difficulty.     

Multiconfigurational quantum chemical methods for molecular systems containing actinides

Recent advances in computational actinide chemistry are reported in this tutorial review. Muticonfigurational quantum chemical methods have been employed to study the gas phase spectroscopy of small actinide molecules. Examples of actinide compounds studied in solution are also presented. Finally the multiple bond in the diuranium molecule and other diactinide compounds is described.     

YinYang atom: a simple combined ab initio quantum mechanical molecular mechanical model

A simple interface is proposed for combined quantum mechanical (QM) molecular mechanical (MM) calculations for the systems where the QM and MM regions are connected through covalent bonds. Within this model, the atom that connects the two regions, called YinYang atom here, serves as an ordinary MM atom to other MM atoms and as a hydrogen-like atom to other QM atoms. Only one new empirical parameter is introduced to adjust the length of the connecting bond and is calibrated with the molecule propanol. This model is tested with the computation of equilibrium geometries and protonation energies for dozens of molecules. Special attention is paid on the influence of MM point charges on optimized geometry and protonation energy, and it is found that it is important to maintain local charge-neutrality in the MM region in order for the accurate calculation of the protonation and deprotonation energies. Overall the simple YinYang atom model yields comparable results to some other QM/MM models.     

The coordination of uranyl in water: a combined quantum chemical and molecular simulation study

The coordination environment of uranyl in water has been studied using a combined quantum mechanical and molecular dynamics approach. Multiconfigurational wave function calculations have been performed to generate pair potentials between uranyl and water. The quantum chemically determined energies have been used to fit parameters in a polarizable force field with an added charge transfer term. Molecular dynamics simulations have been performed for the uranyl ion and up to 400 water molecules. The results show a uranyl ion with five water molecules coordinated in the equatorial plane. The U-O(H(2)O) distance is 2.40 A, which is close to the experimental estimates. A second coordination shell starts at about 4.7 A from the uranium atom. No hydrogen bonding is found between the uranyl oxygens and water. Exchange of waters between the first and second solvation shell is found to occur through a path intermediate between association and interchange. This is the first fully ab initio determination of the solvation of the uranyl ion in water.     

A combined experimental and quantum chemistry study of selenium chemical shift tensors

A comprehensive investigation of selenium chemical shift tensors is presented. Experimentally determined chemical shift tensors were obtained from solid-state 77Se NMR spectra for several organic, organometallic, or inorganic selenium-containing compounds. The first reported indirect spin-spin coupling between selenium and chlorine is observed for Ph(2)SeCl(2) where 1J(77Se,35Cl)iso is 110 Hz. Selenium magnetic shielding tensors were calculated for all of the molecules investigated using zeroth-order regular approximation density functional theory, ZORA DFT. The computations provide the orientations of the chemical shift tensors, as well as a test of the theory for calculating the magnetic shielding interaction for heavier elements. The ZORA DFT calculations were performed with nonrelativistic, scalar relativistic, and scalar with spin-orbit relativistic levels of theory. Relativistic contributions to the magnetic shielding tensor were found to be significant for (NH4)2WSe4 and of less importance for organoselenium, organophosphine selenide, and inorganic selenium compounds containing lighter elements.