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1.
Gary Tresadern Paul F. Faulder M. Paul Gleeson Zubeir Tai Grant MacKenzie Neil A. Burton Ian H. Hillier 《Theoretical chemistry accounts》2003,109(3):108-117
Hybrid quantum mechanical (QM)/molecular mechanical (MM) calculations are used to study two aspects of enzyme catalysis,
Kinetic isotope effects associated with the hydride ion transfer step in the reduction of benzyl alcohol by liver alcohol
dehydrogenase are studied by employing variational transition-state theory and optimised multidimensional tunnelling. With
the smaller QM region, described at the Hartree–Fock ab initio level, together with a parameterised zinc atom charge, good
agreement with experiment is obtained. A comparison is made with the proton transfer in methylamine dehydrogenase. The origin
of the large range in pharmacological activity shown by a series of α-ketoheterocycle inhibitors of the serine protease, elastase,
is investigated by both force field and QM/MM calculations. Both models point to two different inhibition mechanisms being
operative. Initial QM/MM calculations suggest that these are binding, and reaction to form a tetrahedral intermediate, the
latter process occurring for only the more potent set of inhibitors.
Recieved 3 October 2001 / Accepted: 6 September 2002 / Published online: 31 January 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: I. H. Hillier
Acknowledgements. We thank EPSRC and BBSRC for support of the research and D.G. Truhlar for the use of the POLYRATE code. 相似文献
2.
This paper reports a new AM1/d model for phosphorus that can be used to model nucleophilic attack of phosphates relevant
for biological phosphate hydrolysis reactions. The parameters were derived from a quantum dataset calculated with hybrid density-functional
theory [B3LYP/6-311++G(3df,2p)//B3LYP/6-31++G(d,p)] of phosphates and phosphoranes in various charge states, and on transitions
states for nucleophilic attacks. A suite of non-linear optimization methods is outlined for semiempirical parameter development
based on integrated evolutionary (genetic), Monte Carlo simulated annealing and direction set minimization algorithms. The
performance of the new AM1/d model and the standard AM1 and MNDO/d models are compared with the density-functional results.
The results demonstrate that the strategy of developing semiempirical parameters specific for biological reactions offers
considerable promise for application to large-scale biological problems.
Received: 15 January 2002 / Accepted: 6 September 2002 / Published online: 28 March 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: D.M. York e-mail: york@chem.umn.edu
Acknowledgements. D.M.Y. is grateful for financial support provided by the National Institutes of Health (grant 1R01-GM62248-01A1) and the
Donors of The Petroleum Research Fund, administered by the American Chemical Society, and the Minnesota Supercomputing Institute
through a 6-month research scholar award (X.L.). Computational resources were provided by the Minnesota Supercomputing Institute. 相似文献
3.
We present a method to treat the solvent efficiently in hybrid quantum mechanical/molecular mechanical simulations of chemical
reactions in enzymes. The method is an adaptation of an approach developed for molecular-mechanical free-energy simulations.
The charges of each of the exposed ionizable groups are scaled, and the system is simulated in the presence of a limited number
of explicit solvent molecules to obtain a reasonable set of structures. Continuum electrostatics methods are then used to
correct the energies. Variations in the procedure are discussed with an emphasis on modifications from the original protocol.
We illustrate the method by applying it to the study of a hydrolysis reaction in a highly charged system comprising a complex
between the base excision repair enzyme uracil-DNA glycosylase and double-stranded DNA. The resulting adiabatic reaction profile
is in good agreement with experiment, in contrast to that obtained without scaling the charges.
Received: 5 October 2001 / Accepted: 6 September 2002 / Published online: 28 February 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. Karplus e-mail: marci@tammy.harvard.edu 相似文献
4.
Evaluation of an ab initio quantum mechanical/molecular mechanical hybrid-potential link-atom method
Hybrid potentials have become a common tool in the study of many condensed-phase processes and are the subject of much active
research. An important aspect of the formulation of a hybrid potential concerns how to handle covalent bonds between atoms
that are described with different potentials and, most notably, those at the interface of the quantum mechanical (QM) and
molecular mechanical (MM) regions. Several methods have been proposed to deal with this problem, ranging from the simple link-atom
method to more sophisticated hybrid-orbital techniques. Although it has been heavily criticized, the link-atom method has
probably been the most widely used in applications, especially with hybrid potentials that use semiempirical QM methods. Our
aim in this paper has been to evaluate the link-atom method for ab initio QM/MM hybrid potentials and to compare the results
it gives with those of previously published studies. Given its simplicity and robustness, we find that the link-atom method
can produce results of comparable accuracy to other methods as long as the charge distribution on the MM atoms at the interface
is treated appropriately.
Received: 27 September 2002 / Accepted: 21 October 2002 / Published online: 8 January 2003
Correspondence to: M. J. Field e-mail: mjfield@ibs.fr
Acknowledgements. The authors thank the Institut de Biologie Structurale – Jean-Pierre Ebel, the Commissariat à l'Energie Atomique and the
Centre National de la Recherche Scientifique for support of this work. 相似文献
5.
We have investigated the S0 and S1 electronic states in bacteriorhodopsin using a variety of QM/MM levels. The decomposition of the calculated excitation energies
into electronic and electrostatic components shows that the interaction of the chromophore with the protein electric field
increases the excitation energy, while polarization effects are negligible. Therefore, the experimentally observed reduction
in excitation energy from solution phase to protein environment (the Opsin shift) does not come from the electrostatic interaction
with the protein environment, but from either the interaction ofthe chromophore with the solvent or counter ion, or structural
effects. Our high-level ONIOM(TD– B3LYP:Amber) calculation predicts the excitation energy within 8 kcal/mol from experiment,
the discrepancy probably being caused by the neglect of polarization of the protein environment. In addition, we have shown
that the level of optimization is extremely critical for the calculation of accurate excitation energies in bacteriorhodopsin.
Received: 13 October 2001 / Accepted: 6 September 2002 / Published online: 3 February 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: K. Morokuma e-mail: morokuma@emory.edu 相似文献
6.
H. Lee Woodcock Milan Hodošček Paul Sherwood Yong S. Lee Henry F. Schaefer III Bernard R. Brooks 《Theoretical chemistry accounts》2003,109(3):140-148
A replica path method has been developed and extended for use in complex systems involving hybrid quantum/classical (quantum
mechanical/molecular mechanical) coupled potentials. This method involves the definition of a reaction path via replication
of a set of macromolecular atoms. An “important” subset of these replicated atoms is restrained with a penalty function based
on weighted root-mean-square rotation/translation best-fit distances between adjacent (i±1) and next adjacent (i±2) pathway steps. An independent subset of the replicated atoms may be treated quantum mechanically using the computational
engine Gamess-UK. This treatment can be performed in a highly parallel manner in which many dozens of processors can be efficiently
employed. Computed forces may be projected onto a reference pathway and integrated to yield a potential of mean force (PMF).
This PMF, which does not suffer from large errors associated with calculated potential-energy differences, is extremely advantageous.
As an example, the QM/MM replica path method is applied to the study of the Claisen rearrangement of chorismate to prephenate
which is catalyzed by the Bacillus subtilis isolated, chorismate mutase. Results of the QM/MM pathway minimizations yielded an activation enthalpy ΔH
†† of 14.9 kcal/mol and a reaction enthalpy of −19.5 kcal/mol at the B3LYP/6-31G(d) level of theory. The resultant pathway was
compared and contrasted with one obtained using a forced transition approach based on a reaction coordinate constrained repeated
walk procedure (ΔH
†† =20.1 kcal/mol, ΔH
rxn = −20.1 kcal/mol, RHF/4-31G). The optimized replica path results compare favorably to the experimental activation enthalpy
of 12.7±0.4 kcal/mol.
Received: 16 December 2001 / Accepted: 6 September 2002 / Published online: 8 April 2003
Contribution to the Proceedings of the Symposium on Combined QM/MM Methods at the 22nd National Meeting of the American Chemical
Society, 2001.
Correspondence to: H.L. Woodcock e-mail: hlwood@ccqc.uga.edu
Acknowledgements. The authors thank Eric Billings, Xiongwu Wu, and Stephen Bogusz for helpful discussions and related work. The authors also
show grateful appreciation to The National Institutes of Health and The National Science Foundation for support of the current
research. 相似文献
7.
M.M. Hurley J.B. Wright G.H. Lushington W.E. White 《Theoretical chemistry accounts》2003,109(3):160-168
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 相似文献
8.
9.
Pablo A. Molina R. Steven Sikorski Jan H. Jensen 《Theoretical chemistry accounts》2003,109(3):100-107
The relationship between hydrogen bonding and NMR chemical shifts in the catalytic triad of low-pH α-chymotrypsin is investigated
by combined use of the effective fragment potential [(2001) J Phys Chem A 105:293] and ONIOM–NMR [(2000) Chem Phys Lett 317:589] methods. Our study shows that while the His57 Nδ1−H bond is stretched by a relatively modest amount (to about 1.060 ?) this lengthening, combined with the polarization due
to the molecular environment, is sufficient to explain the experimentally observed chemical shifts of 18.2 ppm. Furthermore,
the unusual down-field shift of Hɛ1 (9.2 ppm) observed experimentally is reproduced and shown to be induced by interactions with the C=O group of Ser214 as previously
postulated. The free-energy cost of moving Hδ1 from His57 to Asp102 is predicted to be 5.5 kcal/mol.
Received: 26 September 2001 / Accepted: 6 September 2002 / Published online: 21 January 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: J. H. Jensen e-mail: jan-jensen@uiowa.edu
Acknowledgements. This work was supported by a Research Innovation Award from the Research Corporation and a type G starter grant from the
Petroleum Research Fund. The calculations were performed on IBM RS/6000 workstations obtained through a CRIF grant from the
NSF (CHE-9974502) and on supercomputers at the National Center for Supercomputer Applications at Urbana-Champaign. The authors
are indebted to Visvaldas Kairys for help with the CHARMM program, and to Daniel Quinn for many helpful discussions. 相似文献
10.
Patricia Amara Martin J. Field Cristobal Alhambra Jiali Gao 《Theoretical chemistry accounts》2000,104(5):336-343
Hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials are becoming increasingly important for studying
condensed-phase systems but one of the outstanding problems in the field has been how to treat covalent bonds between atoms
of the QM and MM regions. Recently, we presented a generalized hybrid orbital (GHO) method that was designed to tackle this
problem for hybrid potentials using semiempirical QM methods [Gao et al. (1998) J Phys Chem A 102: 4714–4721]. We tested the method on some small molecules and showed that it performed well when compared to the purely
QM or MM potentials. In this article, we describe the formalism for the determination of the GHO energy derivatives and then
present the results of more tests aimed at validating the model. These tests, involving the calculation of the proton affinities
of some model compounds and a molecular dynamics simulation of a protein, indicate that the GHO method will prove useful for
the application of hybrid potentials to solution-phase macromolecular systems.
Received: 4 October 1999 / Accepted: 18 December 1999 / Published online: 5 June 2000 相似文献
11.
Victor M. Anisimov Nikolay Anikin Vladislav Bugaenko Vladimir Bobrikov Alexey Andreyev 《Theoretical chemistry accounts》2003,109(4):213-219
Accurate electrostatic maps of proteins are of great importance in research of protein interaction with ligands, solvent
media, drugs, and other biomolecules. The large size of real-life proteins imposes severe limitations on computational methods
one can use for obtaining the electrostatic map. Well-known accurate second-order M?ller–Plesset and density functional theory
methods are not routinely applicable to systems larger than several hundred atoms. Conventional semiempirical tools, as less
resource demanding ones, could be an attractive solution but they do not yield sufficiently accurate calculation results with
reference to protein systems, as our analysis demonstrates. The present work performs a thorough analysis of the accuracy
issues of the modified neglect of differential overlap type semiempirical Hamiltonians AM1 and PM3 on example of the calculation
of the molecular electrostatic potential and the dipole moment of natural amino acids. Real capabilities and limitations of
these methods with application to protein modeling are discussed.
Received: 26 April 2002 / Accepted: 19 September 2002 /
Published online: 14 February 2003 相似文献
12.
R. Q. Topper K. Chung C. M. Boelke D. Louie J. S. Kang R. Hannan T. Kiang L. H. Chan 《Theoretical chemistry accounts》2003,109(4):233-238
2-(Acetylamino)fluorene (AAF), a potent mutagen and a prototypical example of the mutagenic aromatic amines, forms covalent
adducts to DNA after metabolic activation in the liver. A benchmark study of AAF is presented using a number of the most widely
used molecular mechanics and semiempirical computational methods and models. The results are compared to higher-level quantum
calculations and to experimentally obtained crystal structures. Hydrogen bonding between AAF molecules in the crystal phase
complicates the direct comparison of gas-phase theoretical calculations with experiment, so Hartree–Fock (HF) and Becke–Perdew
(BP) density functional theory (DFT) calculations are used as benchmarks for the semiempirical and molecular mechanics results.
Systematic conformer searches and dihedral energy landscapes were carried out for AAF using the SYBYL and MMFF94 molecular
mechanics force fields; the AM1, PM3 and MNDO semiempirical quantum mechanics methods; HF using the 3-21G*and 6-31G* basis
sets; and DFT using the nonlocal BP functional and double numerical polarization basis sets. MMFF94, AM1, HF and DFT calculations
all predict the same planar structures, whereas SYBYL, MNDO and PM3 all predict various nonplanar geometries. The AM1 energy
landscape is in substantial agreement with HF and DFT predictions; MMFF94 is qualitatively similar to HF and DFT; and the
MNDO, PM3 and SYBYL results are qualitatively different from the HF and DFT results and from each other. These results are
attributed to deficiencies in MNDO, PM3 and SYBYL. The MNDO, PM3 and SYBYL models may be unreliable for compounds in which
an amide group is immediately adjacent to an aromatic ring.
Received: 26 May 2002 / Accepted: 12 December 2002 /
Published online: 14 February 2003 相似文献
13.
Ibrahim MA 《Journal of chemical information and modeling》2011,51(10):2549-2559
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. 相似文献
14.
David Quiñonero Antonio Frontera Salvador Tomàs Guillem A. Suñer Jeroni Morey Antoni Costa Pau Ballester Pere M. Deyà 《Theoretical chemistry accounts》2000,104(1):50-66
A computational study of the mechanism of host–guest complexation between quaternary ammonium compounds and squaramido-based
tripodal receptors has been carried out. Semiempirical molecular orbital calculations, which are in qualitative agreement
with experimental results have been performed using the PM3 Hamiltonian. Molecular interaction potential (MIP) maps were used
to analyze the suitability of both host and guest binding units for a high-affinity recognition process. MIP calculations
were computed from PM3 wavefunctions of the corresponding ammonium cations and dimethyl squaramide as a model compound for
the hydrogen-bond-acceptor unit of the receptors. MIP analyses are helpful for understanding the host–guest process from the
point of view of the double-complementarity principle.
Received: 23 June 1999 / Accepted: 22 September 1999 / Published online: 17 January 2000 相似文献
15.
Martin Gruebele 《Theoretical chemistry accounts》2003,109(2):53-63
Vibrational energy flow in organic molecules occurs by a multiple-time-scale mechanism that can be modeled by a single exponential
only in its initial stages. The mechanism is a consequence of the hierarchical structure of the vibrational Hamiltonian, which
leads to diffusion of vibrational wavepackets on a manifold with far fewer than the 3N−6 dimensions of the full vibrational state space. The dynamics are controlled by a local density of states, which does not
keep increasing with molecular size. In addition, the number of vibrational coordinates severely perturbed during chemical
reaction is small, leading to preservation of the hierarchical structure at chemically interesting energies. This regularity
opens up the possibility of controlling chemical reactions by controlling the vibrational energy flow. Computationally, laser
control of intramolecular vibrational energy redistribution can be modeled by quantum-classical, or by purely quantum-mechanical
models of the molecule and control field.
Received: 26 July 2002 / Accepted: 30 September 2002 / Published online: 2 December 2002
Electronic Supplementary Material to this paper can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00214-002-0394-2.
Acknowledgements. This work was supported by NSF grant CHE 9986670.
Correspondence to: M. Gruebele e-mail: gruebele@scs.uiuc.edu 相似文献
16.
V. V. Vasilyev A. A. Bliznyuk A. A. Voityuk 《International journal of quantum chemistry》1992,44(5):897-930
A computational approach, which involves the combination of the OPLS force field and molecular orbital MNDO , AM 1, and PM 3 methods, has been developed to describe the effects of a large, molecular mechanically simulated environment on the Hamiltonian of a quantum chemical system. To test the validity of the combined quantum mechanical/molecular mechanical (QM /MM ) potential, a systematic study of the structures and energies of neutral and charged hydrogen-bonded complexes has been carried out, including comparisons with pure semiempirical calculations and available experimental and ab initio data. It is shown that, in many cases, the hybrid QM /MM potential behaves better than do related MNDO /M , AM 1, and PM 3 methods. As a case in point, the draw-back of AM 1 favoring bifurcated H-bonded structures over single ones is not presented in the combined AM 1/OPLS scheme. Possible ways of improvement of the combined QM /MM potential are discussed. © 1992 John Wiley & Sons, Inc. 相似文献
17.
18.
Manuel Montenegro Mireia Garcia-Viloca Àngels González-Lafont José M. Lluch 《Theoretical chemistry accounts》2009,124(3-4):197-215
Protein phosphorylation has been proved to be of great importance in many stages of cell life. In the last few years, its reaction mechanism has been extensively studied. In this work we present the analysis of the performances of several computational methods with different computational costs (from multilevel to semiempirical) to point out the best method to be used at each level in the study of phosphoryl transfer. Finally, we center on the semiempirical methods, and mainly on the AM1/d Hamiltonian with different sets of parameters, which will permit hybrid quantum mechanics/molecular mechanics (QM/MM) free energy calculations on big models at an acceptable computational cost. We have used quite a large set of molecules and model reactions to test the computational methods, reproducing all the chemical steps involved in the mainly accepted reaction pathways for the protein phosphorylation. In the end, we also present the results for an enlarged model, cut out from an entire biological model: we compare the 2-D PES at the B3LYP and AM1/d levels with the purpose of obtaining a correction for the semiempirical method. The AM1/d-PhoT semiempirical parameterization corrected using single-point energy calculations at the B3LYP/MG3S level seems to be suitable to carry out reliable QM/MM calculations of the complete biological system. 相似文献
19.
20.
Titmuss SJ Cummins PL Rendell AP Bliznyuk AA Gready JE 《Journal of computational chemistry》2002,23(14):1314-1322
QM/MM methods have been developed as a computationally feasible solution to QM simulation of chemical processes, such as enzyme-catalyzed reactions, within a more approximate MM representation of the condensed-phase environment. However, there has been no independent method for checking the quality of this representation, especially for highly nonisotropic protein environments such as those surrounding enzyme active sites. Hence, the validity of QM/MM methods is largely untested. Here we use the possibility of performing all-QM calculations at the semiempirical PM3 level with a linear-scaling method (MOZYME) to assess the performance of a QM/MM method (PM3/AMBER94 force field). Using two model pathways for the hydride-ion transfer reaction of the enzyme dihydrofolate reductase studied previously (Titmuss et al., Chem Phys Lett 2000, 320, 169-176), we have analyzed the reaction energy contributions (QM, QM/MM, and MM) from the QM/MM results and compared them with analogous-region components calculated via an energy partitioning scheme implemented into MOZYME. This analysis further divided the MOZYME components into Coulomb, resonance and exchange energy terms. For the model in which the MM coordinates are kept fixed during the reaction, we find that the MOZYME and QM/MM total energy profiles agree very well, but that there are significant differences in the energy components. Most significantly there is a large change (approximately 16 kcal/mol) in the MOZYME MM component due to polarization of the MM region surrounding the active site, and which arises mostly from MM atoms close to (<10 A) the active-site QM region, which is not modelled explicitly by our QM/MM method. However, for the model where the MM coordinates are allowed to vary during the reaction, we find large differences in the MOZYME and QM/MM total energy profiles, with a discrepancy of 52 kcal/mol between the relative reaction (product-reactant) energies. This is largely due to a difference in the MM energies of 58 kcal/mol, of which we can attribute approximately 40 kcal/mol to geometry effects in the MM region and the remainder, as before, to MM region polarization. Contrary to the fixed-geometry model, there is no correlation of the MM energy changes with distance from the QM region, nor are they contributed by only a few residues. Overall, the results suggest that merely extending the size of the QM region in the QM/MM calculation is not a universal solution to the MOZYME- and QM/MM-method differences. They also suggest that attaching physical significance to MOZYME Coulomb, resonance and exchange components is problematic. Although we conclude that it would be possible to reparameterize the QM/MM force field to reproduce MOZYME energies, a better way to account for both the effects of the protein environment and known deficiencies in semiempirical methods would be to parameterize the force field based on data from DFT or ab initio QM linear-scaling calculations. Such a force field could be used efficiently in MD simulations to calculate free energies. 相似文献