Comparative quantum mechanics/molecular mechanics (QM/MM) and density functional theory calculations on the oxo-iron species of taurine/alpha-ketoglutarate dioxygenase

We present here the first quantum mechanical/molecular mechanics (QM/MM) studies of taurine/alpha-ketoglutarate dioxygenase (TauD) enzymes. Our studies are focused on the chemical properties of the oxo-iron species and the effect of the protein environment on its structural and electronic behavior. Although the active site region of TauD is very polar with many key hydrogen bonding interactions and salt bridges, the actual effect of the protein environment on the ordering and relative energies of the possible spin state structures is found to be quite small. Optimized geometries are very close to ones observed with density functional theory models that did not take the protein environment into consideration. The calculations show that protonation of the histidine ligands of iron is essential to reproduce the correct electronic representations of the enzyme. Hydroxylation studies of taurine by the oxo-iron active species predict that it is a very efficient catalyst that reacts with substrates via low reaction barriers.     

Structure and electronic properties of hydrated mesityl oxide: a sequential quantum mechanics/molecular mechanics approach

The hydration of mesityl oxide (MOx) was investigated through a sequential quantum mechanics/molecular mechanics approach. Emphasis was placed on the analysis of the role played by water in the MOx syn–anti equilibrium and the electronic absorption spectrum. Results for the structure of the MOx–water solution, free energy of solvation and polarization effects are also reported. Our main conclusion was that in gas-phase and in low-polarity solvents, the MOx exists dominantly in syn-form and in aqueous solution in anti-form. This conclusion was supported by Gibbs free energy calculations in gas phase and in-water by quantum mechanical calculations with polarizable continuum model and thermodynamic perturbation theory in Monte Carlo simulations using a polarized MOx model. The consideration of the in-water polarization of the MOx is very important to correctly describe the solute–solvent electrostatic interaction. Our best estimate for the shift of the π–π^* transition energy of MOx, when it changes from gas-phase to water solvent, shows a red-shift of −2,520 ± 90 cm⁻¹, which is only 110 cm⁻¹ (0.014 eV) below the experimental extrapolation of −2,410 ± 90 cm⁻¹. This red-shift of around −2,500 cm⁻¹ can be divided in two distinct and opposite contributions. One contribution is related to the syn → anti conformational change leading to a blue-shift of ~1,700 cm⁻¹. Other contribution is the solvent effect on the electronic structure of the MOx leading to a red-shift of around −4,200 cm⁻¹. Additionally, this red-shift caused by the solvent effect on the electronic structure can by composed by approximately 60 % due to the electrostatic bulk effect, 10 % due to the explicit inclusion of the hydrogen-bonded water molecules and 30 % due to the explicit inclusion of the nearest water molecules.     

Quantum mechanics and mixed quantum mechanics/molecular mechanics simulations of model nerve agents with acetylcholinesterase

 The accurate modeling of biological processes presents major computational difficulties owing to the inherent complexity of the macromolecular systems of interest. Simulations of biochemical reactivity tend to require highly computationally intensive quantum mechanical methods, but localized chemical effects tend to depend significantly on properties of the extended biological environment – a regime far more readily examined with lower-level classical empirical models. Mixed quantum/classical techniques are gaining in popularity as a means of bridging these competing requirements. Here we present results comparing two quantum mechanics/molecular mechanics implementations (the SIMOMM technique of Gordon et al. as implemented in GAMESS, and the ONIOM technique of Morokuma et al. found in Gaussian 98) as performed on the enzyme acetylcholinesterase and model nerve agents. This work represents part of the initial phase of a DoD HPCMP Challenge project in which we are attempting to reliably characterize the biochemical processes responsible for nerve agent activity and inhibition, thereby allowing predictions on compounds unrelated to those already studied. Received: 10 October 2001 / Accepted: 13 November 2002 / Published online: 1 April 2003 Contribution to the Proceedings of the Symposium on Combined QM/MM Methods at the 222nd National Meeting of the American Chemical Society, 2001 Correspondence to: M. M. Hurley e-mail: hurley@arl.army.mil     

Microscopic and macroscopic polarization within a combined quantum mechanics and molecular mechanics model

A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to macroscopic susceptibilities directly comparable with experimental results. By separating the discrete local field into two distinct contribution we define two different microscopic properties, the so-called solute and effective properties. The solute properties account for the pure solvent effects, i.e., effects even when the macroscopic electric field is zero, and the effective properties account for both the pure solvent effects and the effect from the induced dipoles in the solvent due to the macroscopic electric field. We present results for the linear and nonlinear polarizabilities of water and acetonitrile both in the gas phase and in the liquid phase. For all the properties we find that the pure solvent effect increases the properties whereas the induced electric field decreases the properties. Furthermore, we present results for the refractive index, third-harmonic generation (THG), and electric field induced second-harmonic generation (EFISH) for liquid water and acetonitrile. We find in general good agreement between the calculated and experimental results for the refractive index and the THG susceptibility. For the EFISH susceptibility, however, the difference between experiment and theory is larger since the orientational effect arising from the static electric field is not accurately described.     

Density functional self-consistent quantum mechanics/molecular mechanics theory for linear and nonlinear molecular properties: Applications to solvated water and formaldehyde

A combined quantum mechanics/molecular mechanics (QM/MM) method is described, where the polarization between the solvent and solute is accounted for using a self-consistent scheme linear in the solvent polarization. The QM/MM method is implemented for calculation of energies and molecular response properties including the calculation of linear and quadratic response functions using the density-functional theory (DFT) and the Hartree-Fock (HF) theory. Sample calculations presented for ground-state energies, first-order ground-state properties, excitation energies, first-order excited state properties, polarizabilities, first-hyperpolarizabilities, and two-photon absorptions strengths of formaldehyde suggests that DFT may in some cases be a sufficiently reliable alternative to high-level theory, such as coupled-cluster (CC) theory, in modeling solvent shifts, whereas results obtained with the HF wave function deviate significantly from the CC results. Calculations carried out on water gives results that also are comparable with CC calculations in accuracy for ground-state and first-order properties. However, to obtain such accuracy an exchange-correlation functional capable of describing the diffuse Rydberg states must be chosen.     

Electronic properties of liquid ammonia: a sequential molecular dynamics/quantum mechanics approach

The electronic properties of liquid ammonia are investigated by a sequential molecular dynamics/quantum mechanics approach. Quantum mechanics calculations for the liquid phase are based on a reparametrized hybrid exchange-correlation functional that reproduces the electronic properties of ammonia clusters [(NH3)n; n=1-5]. For these small clusters, electron binding energies based on Green's function or electron propagator theory, coupled cluster with single, double, and perturbative triple excitations, and density functional theory (DFT) are compared. Reparametrized DFT results for the dipole moment, electron binding energies, and electronic density of states of liquid ammonia are reported. The calculated average dipole moment of liquid ammonia (2.05+/-0.09 D) corresponds to an increase of 27% compared to the gas phase value and it is 0.23 D above a prediction based on a polarizable model of liquid ammonia [Deng et al., J. Chem. Phys. 100, 7590 (1994)]. Our estimate for the ionization potential of liquid ammonia is 9.74+/-0.73 eV, which is approximately 1.0 eV below the gas phase value for the isolated molecule. The theoretical vertical electron affinity of liquid ammonia is predicted as 0.16+/-0.22 eV, in good agreement with the experimental result for the location of the bottom of the conduction band (-V 0=0.2 eV). Vertical ionization potentials and electron affinities correlate with the total dipole moment of ammonia aggregates.     

Development of a model for the rational design of molecular imprinted polymer: Computational approach for combined molecular dynamics/quantum mechanics calculations

A new rational approach for the preparation of molecularly imprinted polymer (MIP) based on the combination of molecular dynamics (MD) simulations and quantum mechanics (QM) calculations is described in this work. Before performing molecular modeling, a virtual library of functional monomers was created containing forty frequently used monomers. The MD simulations were first conducted to screen the top three monomers from virtual library in each porogen-acetonitrile, chloroform and carbon tetrachloride. QM simulations were then performed with an aim to select the optimum monomer and progen solvent in which the QM simulations were carried out; the monomers giving the highest binding energies were chosen as the candidate to prepare MIP in its corresponding solvent. The acetochlor, a widely used herbicide, was chosen as the target analyte. According to the theoretical calculation results, the MIP with acetochlor as template was prepared by emulsion polymerization method using N,N-methylene bisacrylamide (MBAAM) as functional monomer and divinylbenzene (DVB) as cross-linker in chloroform. The synthesized MIP was then tested by equilibrium-adsorption method, and the MIP demonstrated high removal efficiency to the acetochlor. Mulliken charge distribution and ¹H NMR spectroscopy of the synthesized MIP provided insight on the nature of recognition during the imprinting process probing the governing interactions for selective binding site formation at a molecular level. We think the computer simulation method first proposed in this paper is a novel and reliable method for the design and synthesis of MIP.     

Using molecular dynamics and quantum mechanics calculations to model fluorescence observables

We provide a critical examination of two different methods for generating a donor-acceptor electronic coupling trajectory from a molecular dynamics (MD) trajectory and three methods for sampling that coupling trajectory, allowing the modeling of experimental observables directly from the MD simulation. In the first coupling method we perform a single quantum-mechanical (QM) calculation to characterize the excited state behavior, specifically the transition dipole moment, of the fluorescent probe, which is then mapped onto the configuration space sampled by MD. We then utilize these transition dipoles within the ideal dipole approximation (IDA) to determine the electronic coupling between the probes that mediates the transfer of energy. In the second method we perform a QM calculation on each snapshot and use the complete transition densities to calculate the electronic coupling without need for the IDA. The resulting coupling trajectories are then sampled using three methods ranging from an independent sampling of each trajectory point (the independent snapshot method) to a Markov chain treatment that accounts for the dynamics of the coupling in determining effective rates. The results show that the IDA significantly overestimates the energy transfer rate (by a factor of 2.6) during the portions of the trajectory in which the probes are close to each other. Comparison of the sampling methods shows that the Markov chain approach yields more realistic observables at both high and low FRET efficiencies. Differences between the three sampling methods are discussed in terms of the different mechanisms for averaging over structural dynamics in the system. Convergence of the Markov chain method is carefully examined. Together, the methods for estimating coupling and for sampling the coupling provide a mechanism for directly connecting the structural dynamics modeled by MD with fluorescence observables determined through FRET experiments.     

Utilization of deformations in molecular quantum chemistry and application to density functional theory

The aim of this article is to present in a way accessible to most quantum chemists a general mathematical method which consists in deforming wave functions and density functions (in the spirit of the local scaling transformation). This deformation method allows us to obtain several new results, including a characterization of the set of wave functions that have the same given density function (which gives a new insight on a result of G. Zumbach and K. Maschke, Phys. Rev. A 28 , 544 (1983)) and an N-representability result where symmetry is taken into account. We also propose new theoretical ways to generate approximations of the exact density functional and give a numerical example. © 1998 John Wiley & Sons, Inc. Int J Quant Chem 68: 221–231, 1998     

PVM-AMBER: A parallel implementation of the AMBER molecular mechanics package for workstation clusters

A parallel version of the popular molecular mechanics package AMBER suitable for execution on workstation clusters has been developed. Computer-intensive portions of molecular dynamics or free-energy perturbation computations, such as nonbonded pair list generation or calculation of nonbonded energies and forces, are distributed across a collection of Unix workstations linked by Ethernet or FDDI connections. This parallel implementation utilizes the message-passing software PVM (Parallel Virtual Machine) from Oak Ridge National Laboratory to coordinate data exchange and processor synchronization. Test simulations performed for solvated peptide, protein, and lipid bilayer systems indicate that reasonable parallel efficiency (70–90%) and computational speedup (2–5 × serial computer runtimes) can be achieved with small workstation clusters (typically six to eight machines) for typical biomolecular simulation problems. PVM-AMBER is also easily and rapidly portable to different hardware platforms due to the availability of PVM for numerous computers. The current version of PVM-AMBER has been tested successfully on Silicon Graphics, IBM RS6000, DEC ALPHA, and HP 735 workstation clusters and heterogeneous clusters of these machines, as well as on CRAY T3D and Kendall Square KSR2 parallel supercomputers. Thus, PVM-AMBER provides a simple and cost-effective mechanism for parallel molecular dynamics simulations on readily available hardware platforms. Factors that affect the efficiency of this approach are discussed. © 1995 by John Wiley & Sons, Inc.     

Interpretation of nuclear resonant vibrational spectra of rubredoxin using a combined quantum mechanics and molecular mechanics approach

Nuclear resonant vibrational spectra of the reduced and oxidized form of a mutant of rubredoxin from Pyrococcus abyssii were measured and are compared with simulated spectra that were calculated by a combined quantum mechanics (QM) and molecular mechanics (MM) method. Density functional theory was used for the QM level. Calculations were performed for different models of rubredoxin. Realistic spectra were simulated with reduced models that include at least the iron center, the four cysteins coordinating it, and the residues connected to the cysteins together with a QM layer that comprises the first two coordination shells of the iron center. Larger QM layers did not lead to significant changes of the simulated spectra.     

Structure and ultrafast dynamics of liquid water: a quantum mechanics/molecular mechanics molecular dynamics simulations study

A quantum mechanics/molecular mechanics molecular dynamics simulation was performed for liquid water to investigate structural and dynamical properties of this peculiar liquid. The most important region containing a central reference molecule and all nearest surrounding molecules (first coordination shell) was treated by Hartree-Fock (HF), post-Hartree-Fock [second-order Moller-Plesset perturbation theory (MP2)], and hybrid density functional B3LYP [Becke's three parameter functional (B3) with the correlation functional of Lee, Yang, and Parr (LYP)] methods. In addition, another HF-level simulation (2HF) included the full second coordination shell. Site to site interactions between oxygen-oxygen, oxygen-hydrogen, and hydrogen-hydrogen atoms of all ab initio methods were compared to experimental data. The absence of a second peak and the appearance of a shoulder instead in the gO-O graph obtained from the 2HF simulation is notable, as this feature has been observed so far only for pressurized or heated water. Dynamical data show that the 2HF procedure compensates some of the deficiency of the HF one-shell simulation, reducing the difference between correlated (MP2) and HF results. B3LYP apparently leads to too rigid structures and thus to an artificial slow down of the dynamics.     

A sequential molecular mechanics/quantum mechanics study of the electronic spectra of amides

We report gas-phase electronic spectra of formamide, N-methyformamide, acetamide, and N-methylacetamide at 300 K calculated using a combination of classical molecular dynamics and time-dependent density functional theory (TDDFT). In comparison to excitation energies computed using the global minima structures, the valence npi* and pi(nb)pi* states show a significant red-shift of 0.1-0.35 eV, while smaller shifts are found for the n3s and pi(nb)3s Rydberg states. In this work, we have identified the physical origin of these shifts arising from variations of the molecular structure. We present simple relationships between key geometrical parameters and spectral shifts. Consequently, electronic spectra can be generated directly from ground-state structures, without additional quantum chemical calculations. The electronic spectrum of formamide in aqueous solution is computed using TDDFT using an explicit solvent model. This provides a quantitative determination of the condensed-phase spectrum. In general, this study shows that temperature effects can change the predicted excitation energies significantly and demonstrates how electronic spectra at elevated temperatures can be computed in a computationally efficient way.     

An efficient method for the calculation of quantum mechanics/molecular mechanics free energies

The combination of quantum mechanics (QM) with molecular mechanics (MM) offers a route to improved accuracy in the study of biological systems, and there is now significant research effort being spent to develop QM/MM methods that can be applied to the calculation of relative free energies. Currently, the computational expense of the QM part of the calculation means that there is no single method that achieves both efficiency and rigor; either the QM/MM free energy method is rigorous and computationally expensive, or the method introduces efficiency-led assumptions that can lead to errors in the result, or a lack of generality of application. In this paper we demonstrate a combined approach to form a single, efficient, and, in principle, exact QM/MM free energy method. We demonstrate the application of this method by using it to explore the difference in hydration of water and methane. We demonstrate that it is possible to calculate highly converged QM/MM relative free energies at the MP2/aug-cc-pVDZ/OPLS level within just two days of computation, using commodity processors, and show how the method allows consistent, high-quality sampling of complex solvent configurational change, both when perturbing hydrophilic water into hydrophobic methane, and also when moving from a MM Hamiltonian to a QM/MM Hamiltonian. The results demonstrate the validity and power of this methodology, and raise important questions regarding the compatibility of MM and QM/MM forcefields, and offer a potential route to improved compatibility.     

Understanding the optical spectroscopy of amphiphilic molecular rectifiers: a density functional approach

We present results of first principles density functional theory calculations of the electronic and atomic structural properties of model Z-type Langmuir-Blodgett (LB) layers comprising amphiphilic quinolinium tricyanoquinodimethanide (Q3CNQ) chromophores. We find that the chromophore electronic ground state is not as clearly "zwitterionic" as required by models to explain electrical rectification purportedly seen in such systems. The computed visible region transitions are not what have been assumed to be the intervalence charge transfer bands seen in the visible region of molecules in Z-type LB films. Our own LB deposition and spectroscopic studies suggest that almost all visible region features previously seen may be ascribed to aggregates. The calculated lowest energy electronic excitation between HOMO and LUMO levels, which is located in the near infrared region, has a transition moment aligned approximately 9° off the molecular long axis, and has a normalized oscillator strength of 1 order of magnitude higher than those of the visible region transitions. This most dominant feature has been neglected from discussions of Langmuir-Blodgett layer rectification but our own deposition studies show no sign of this feature, indicating that the structure of the modeled system differs from that of typical experimental structures. The model indicates that such idealized LB layer structures cannot confidently be invoked to explain their experimental optical or electrical properties.     

Application of the finite element method to molecular quantum mechanics

We present a general formalism of the finite element method and its computational aspects that influence the solution accuracy of spectral quantum mechanical problems. The possibilities of the method are demonstrated using as an example inversion vibrational spectra of structurally non-rigid complexes.High Energy Physics Institute, Protvino. I. V. Kurchatov, Atomic Energy Institute, Moscow. Translated from Teoreticheskaya i Eksperimental'naya Khimiya, Vol. 27, No. 4, pp. 442–446. July–August, 1991. Original article submitted April 4, 1991.     

GridMol2.0: Implementation and application of linear-scale quantum mechanics methods and molecular visualization

GridMol is a “one-stop” platform for molecular structure building, scientific computing, and molecular visualization aided by a high-performance computing environment. GridMol version 2.0 introduces two unique features: the first is fragment-based linear-scaling quantum chemistry methods, such as molecular fractionation with conjugate caps and fragment molecular orbital methods; the second is that GridMol enables users to visualize molecular geometries along a geometry optimization and an intrinsic reaction coordinate calculation. Compared with version 1.0, fragment-based linear-scaling quantum chemistry methods implemented in GridMol version 2.0 can be used as a useful tool for performing quantum calculations for large molecular systems to explore the mechanisms involved in protein-ligand or targeted drug interactions.     

Hybrid density functional theory/molecular mechanics calculations of two-photon absorption of dimethylamino nitro stilbene in solution

The dimethylamino nitro stilbene (DANS) molecule is studied for exploring solvent effects on two-photon absorption using the quantum mechanical/molecular mechanical (QM/MM) response theory approach, where the quantum part is represented by density functional theory. We have explored the role of geometrical change of the chromophore in solution, the importance of taking a dynamical average over the sampled structures and the role of a granular representation of the polarization and electrostatic interactions with the classically described medium. The line shape function was simulated by the QM/MM technique thereby allowing for non-empirical prediction of the absolute two-photon cross section. We report a maximum in the TPA cross section for a medium of intermediate solvent polarity (i.e. in chloroform) and provide the grounds for an explanation of this effect which recently has been experimentally observed for a series of charge transfer species in solvents of different polarity. The calculations of absorption energies reproduce well the positive solvatochromic behavior of DANS and are in good agreement with experimental spectra available for the chloroform and DMSO solvents. In line with recent development of the QM/MM response technique for color modeling, we find this methodology to offer a versatile tool to predict and analyze two-photon absorption phenomena taking place within a medium.