QM/MM: what have we learned, where are we, and where do we go from here?

Lin, Hai; Truhlar, Donald G.

doi:10.1007/s00214-006-0143-z

Cited by 1,091 publications

(893 citation statements)

References 217 publications

(172 reference statements)

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“…In this QM/MM approach, QM and MM energies and forces are added, ensuring that no terms are double-counted [5,6,7,8]. Several different approaches are available to treat the electrostatic interactions between the QM and MM systems and the positions where covalent bonds in the MM system are broken to form the truncated QM system (junctions) [6,7].…”

Section: Introductionmentioning

confidence: 99%

Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins

Sumner

Söderhjelm

Ryde

2013

J. Chem. Theory Comput.

120

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We have examined the effect of geometry optimisation on energies calculated with the quantum-mechanical (QM) cluster, the combined QM and molecular-mechanics (QM/MM), the big-QM approaches (very large single-point QM calculations taken from QM/MMoptimised structures, including all atoms within 4.5 Å of the minimal active site, all buried charged groups in the protein, and truncations moved at least three residues away from the active site). We study a simple proton-transfer reaction between His-79 and Cys-546 in the active site of [Ni,Fe] hydrogenase and optimise QM systems of 50 different sizes (56-362 atoms). Geometries optimised with QM/MM are stable and reliable, whereas QM-cluster optimisations give larger changes in the structures and sometimes lead to large distortions in the active site if some hydrogen-bond partners to the metal ligands are omitted. Keeping 2-3 atoms for each truncated residue (rather than one) fixed in the optimisation improves the results, but does not solve all problems for the QM-cluster optimisations. QM-cluster energies in vacuum and a continuum solvent are insensitive to the geometry optimisations with a mean absolute change upon the optimisations of only 4-7 kJ/mol. This shows that geometry optimisations do not improve the convergence of QM-cluster calculations -there is still a ~60 kJ/mol difference between calculations in which groups have been added to the QM system according to their distance to the active site or based on QM/MM free-energy components. QM/MM energies do not show such a difference, but they converge rather slowly with respect to the size of the QM system, although the convergence is improved by moving away truncations from the active site. The big-QM energies are stable over the 50 different optimised structures, 57±1 kJ/mol, although some smaller trends can be discerned. This shows that both QM-cluster geometries and energies should be interpreted with caution. Instead, we recommend QM/MM for geometry optimisations and energies calculated by the big-QM approach.Key Words: Quantum mechanical cluster calculations, QM/MM, geometry optimisation, density-functional theory, [Ni,Fe] hydrogenase. 2 IntroductionDuring the latest two decades, quantum mechanical (QM) calculations have been established as an important and powerful complement to experiments for the study of biochemical reactions [1,2,3,4,5,6,7,8]. In particular, it has been shown that QM calculations can give structures of active sites with an accuracy that is better than what is obtained in lowand medium-resolution crystal structures [9], and they can provide structures of transition states of putative enzyme reactions, which are hard to study experimentally. The calculations also give energies of the transition states and intermediates, which can be used to compare different putative reaction mechanisms.Two approaches are used for such calculations. In the QM cluster approach, the most important residues of the active site (typically 50-200 atoms) are cut out of the enzyme [1,2,3,4]. The geom...

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Section: Introductionmentioning

confidence: 99%

Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins

Sumner

Söderhjelm

Ryde

2013

J. Chem. Theory Comput.

120

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“…As common in hybrid quantum mechanical/molecular mechanical (QM/MM) approaches, [17][18][19][20][21][22][23] the simulation systems is separated into a high-and a low-level zone. While the interactions within the first region are treated by application of a suitable quantum chemical technique, classical potential functions are considered to be sufficiently accurate to describe the remaining part of the system.…”

Section: Quantum Mechanical Charge Field Molecular Dynamics (Qmcf Md)mentioning

confidence: 99%

Structure and water exchange of the hydrated thiosulfate ion in aqueous solution using QMCF MD simulation and large angle X-ray scattering

et al. 2014

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, x=3-8, and radial distribution functions from simulation of the thiosulfate ion, and from experimental LAXS data on the hydrated peroxodisulfate ion in water. Graphical Abstract SynopsisExperimental and simulation data of the thiosulfate ion show large similarities in hydration structure and mechanism with the sulfate ion but with weaker hydration of the terminal sulfur atom in thiosulfate. AbstractTheoretical ab initio quantum mechanical charge field molecular dynamics (QMCF MD) has been applied in conjunction with experimental large angle X-ray scattering (LAXS) to study the structure and dynamics of the hydrated thiosulfate ion, S 2 O 3 2-, in aqueous solution. The S-O and S C -S T bond distances have been determined to 1.479(5) and 2.020(6) Å by LAXS and to 1.478 and 2.017 Å by QMCF MD simulations, which are slightly longer than the mean values found in the solid state, 1.467 and 2.002 Å, respectively. This is due to the hydrogen bonds formed at hydration.The water dynamics show that water molecules are exchanged at the hydrated oxygen and sulfur atoms, and that the water exchange is ca. 50% faster at the sulfur atom than at the oxygens atoms with mean residence times,  0.5 , of 2.4 and 3.6 ps, respectively. From this point of view the water exchange dynamics mechanism resembles the sulfate ion, while it is significantly different from the sulfite ion. This shows that the lone electron-pair in the sulfite ion has a much larger impact on the water exchange dynamics than a substitution of an oxygen atom for a sulfur one. The LAXS data did give mean S C ⋅⋅⋅O aq1 and S C ⋅⋅⋅O aq2 distances of 3.66(2) and 4.36(10) Å, respectively, and S C -O thio and O thio ⋅⋅⋅O aq1 , S C -S T and S T ⋅⋅⋅O aq2 distances of 1.479(5), 2.845(10), 2.020(6) and 3.24(5) Å, respectively, giving S C -O thio ⋅⋅⋅O aq1 and S C -S T ⋅⋅⋅O aq2 angles close 110 o , strongly indicating a tetrahedral geometry around the terminal thiosulfate sulfur and the oxygens, and thereby, three water molecules are hydrogen bound to each of them. The hydrogen bonds between thiosulfate oxygens and the hydrating water molecules are stronger and with longer mean residence times than between water molecules in the aqueous bulk, while the opposite is true for the hydrogen bonds between the terminal thiosulfate sulfur and the hydrating water molecules. The hydration of all oxo sulfur ions are discussed using the detailed observations for the sulfate, thiosulfate and sulfite ions, and the structure of the hydrated peroxodisulfate ion, S 2 O 8 2-, in aqueous solution has been determined by means of LAXS to support the general observations. The mean S-O bond distances are 1.448(2) and 1.675(5) Å to the oxo and peroxo oxygens, respectively.

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“…6 for a recent review), there is much need to reduce the prefactors for performing calculations on molecular systems, in particular, in following MD trajectories or in scanning, e.g., interaction domains in complex systems. Although there has been some progress in reducing the necessary quantum-chemical (QM) sphere by combination with simple empirical molecularmechanical (MM) methods in so-called QM/MM schemes, [7][8][9][10] it has been shown crucial to systematically converge the QM sphere and to typically include large QM spheres of more than 300-1000 atoms for reliable results, [11][12][13][14][15] so that the prefactors of the calculations still remain large.…”

Section: Introductionmentioning

confidence: 99%

An extrapolation method for the efficient calculation of molecular response properties within Born–Oppenheimer molecular dynamics

Flaig

Ochsenfeld

2013

Phys. Chem. Chem. Phys.

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The calculation of molecular response properties in dynamic molecular systems is a major challenge that requires sampling over many steps of, e.g., Born-Oppenheimer molecular dynamics (BO-MD) simulations. We present an extrapolation scheme to accelerate such calculations for multiple steps within BO-MD trajectories or equivalently within other sampling methods of conformational space. The extrapolation scheme is related to the one introduced by Pulay and Fogarasi [Chem. Phys. Lett., 2004, 386, 272] for self-consistent field (SCF) energy calculations. We extend the extrapolation to the quantities within our density matrix-based Laplace-transformed coupled perturbed SCF (DL-CPSCF) method that allows for linear-scaling calculations of response properties for large molecular systems. Here, we focus on the example of calculating NMR chemical shifts for which the number of required DL-CPSCF iterations reduces by roughly 40-70%.

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QM/MM: what have we learned, where are we, and where do we go from here?

Cited by 1,091 publications

References 217 publications

Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins

Effect of Geometry Optimizations on QM-Cluster and QM/MM Studies of Reaction Energies in Proteins

Structure and water exchange of the hydrated thiosulfate ion in aqueous solution using QMCF MD simulation and large angle X-ray scattering

An extrapolation method for the efficient calculation of molecular response properties within Born–Oppenheimer molecular dynamics

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