Improving the <scp>Q2MM</scp> method for transition state force field modeling

Limé, Elaine; Norrby, Per‐Ola

doi:10.1002/jcc.23797

Cited by 10 publications

(18 citation statements)

References 22 publications

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“…To study this question, we used the Q2MM method described elsewhere 20,21,23,24,26–28 to optimize MM3* parameters for 2 . For comparison purposes, we also parametrized 1 .…”

Section: Resultsmentioning

confidence: 99%

Anomeric Effects in Sulfamides

et al. 2016

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Sulfamides, together with their simpler sulfonamide analogs, are common functional groups in a significant number of biologically active compounds. This is partly due to their unique electronic structure and conformational behavior, which mimics the tetrahedral intermediate involved in many proteases, esterases, and related enzymes. Here, the origin of these unique structural elements are analyzed in the context of a coupled, double anomeric effect using DFT calculations, including conformational scans, and NBO analysis. It is shown that these coupled interactions can be implicitly parametrized in MM3* type force fields using the quantum-guided molecular mechanics (Q2MM) method, yielding accurate force field parameters for molecular mechanics studies of sulfamides and sulfonamides.

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“…To study this question, we used the Q2MM method described elsewhere 20,21,23,24,26–28 to optimize MM3* parameters for 2 . For comparison purposes, we also parametrized 1 .…”

Section: Resultsmentioning

confidence: 99%

Anomeric Effects in Sulfamides

et al. 2016

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“…Flipping this curvature is possible by decomposing the Hessian into its corresponding eigenvectors V and eigenvalues S and replacing the negative eigenvalue of the TS with a large positive value or fitting directly to the eigenmodes and eigenvectors while ignoring the eigenmode with negative eigenvalues. 24 …”

Section: The Quantum-guided Molecular Mechanics (Q2mm) Methodsmentioning

confidence: 99%

Prediction of Stereochemistry using Q2MM

et al. 2016

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ConspectusThe standard method of screening ligands for selectivity in asymmetric, transition metal-catalyzed reactions requires experimental testing of hundreds of ligands from ligand libraries. This “trial and error” process is costly in terms of time as well as resources and, in general, is scientifically and intellectually unsatisfying as it reveals little about the underlying mechanism behind the selectivity. The accurate computational prediction of stereoselectivity in enantioselective catalysis requires adequate conformational sampling of the selectivity-determining transition state but has to be fast enough to compete with experimental screening techniques to be useful for the synthetic chemist. Although electronic structure calculations are accurate and general, they are too slow to allow for sampling or fast screening of ligand libraries. The combined requirements can be fulfilled by using appropriately fitted transition state force fields (TSFFs) that represent the transition state as a minimum and allow fast conformational sampling using Monte Carlo.Quantum-guided molecular mechanics (Q2MM) is an automated force field parametrization method that generates accurate, reaction-specific TSFFs by fitting the functional form of an arbitrary force field using only electronic structure calculations by minimization of an objective function. A key feature that distinguishes the Q2MM method from many other automated parametrization procedures is the use of the Hessian matrix in addition to geometric parameters and relative energies. This alleviates the known problems of overfitting of TSFFs. After validation of the TSFF by comparison to electronic structure results for a test set and available experimental data, the stereoselectivity of a reaction can be calculated by summation over the Boltzman-averaged relative energies of the conformations leading to the different stereoisomers.The Q2MM method has been applied successfully to perform virtual ligand screens on a range of transition metal-catalyzed reactions that are important from both an industrial and an academic perspective. In this Account, we provide an overview of the continued improvement of the prediction of stereochemistry using Q2MM-derived TSFFs using four examples from different stages of development: (i) Pd-catalyzed allylation, (ii) OsO4-catalyzed asymmetric dihydroxylation (AD) of alkenes, (iii) Rh-catalyzed hydrogenation of enamides, and (iv) Ru-catalyzed hydrogenation of ketones. In the current form, correlation coefficients of 0.8–0.9 between calculated and experimental ee values are typical for a wide range of substrate–ligand combinations, and suitable ligands can be predicted for a given substrate with ∼80% accuracy. Although the generation of a TSFF requires an initial effort and will therefore be most useful for widely used reactions that require frequent screening campaigns, the method allows for a rapid virtual screen of large ligand libraries to focus experimental efforts on the most promising substrate–ligand combinations.

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“…Deviations between the two matrices are summed into an objective function to be minimized during parameterization. 54 This will produce a positive definite force field, now with fewer artifacts from the enforced positive eigenvalue (the force constants can now achieve “natural” values), but the softer mode can instead introduce undesired distortions along the reaction coordinate. 41…”

Section: Historical Background To Q2mmmentioning

confidence: 99%

“…The diagonal elements should contain a single negative eigenvalue (reaction coordinate), which has a weight of zero, allowing for a “natural fit” of relevant parameters. 54 All other diagonal elements represent the other normal modes and are assigned a weight of 0.1 kJ/mol −1 Å −2 amu −1 . A good fit of the diagonal elements is what allows a Q2MM force field to represent the energy cost of distortions perpendicular to the reaction coordinate with high accuracy, an essential element for accurate predictions.…”

Section: Deriving Q2mm Force Fieldsmentioning

confidence: 99%

“…The best that can be done within the Q2MM method is to apply a high force constant to ensure all such bonds come out at approximately the same value. 54 For most other bonds, a close reproduction should be achievable. Alternatively, bonds have to be environment-dependent, and different parameter sets are used depending on the surrounding structure.…”

Section: Deriving Q2mm Force Fieldsmentioning

confidence: 99%

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Application of Q2MM to predictions in stereoselective synthesis

et al. 2018

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Quantum-Guided Molecular Mechanics (Q2MM) can be used to derive transition state force fields (TSFFs) that allow the fast and accurate predictions of stereoselectivity for a wide range of catalytic enantioselective reactions. The basic ideas behind the derivation of TSFFs using Q2MM are discussed and the steps involved in obtaining a TSFF using the Q2MM code, publically available at github.com/q2mm, are shown. The applicability for a range of reactions, including several non-standard applications of Q2MM, is demonstrated. Future developments of the method are also discussed.

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Improving the Q2MM method for transition state force field modeling

Cited by 10 publications

References 22 publications

Anomeric Effects in Sulfamides

Anomeric Effects in Sulfamides

Prediction of Stereochemistry using Q2MM

Application of Q2MM to predictions in stereoselective synthesis

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