| 1. |
- Caldararu, Octav, et al.
(författare)
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Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods
- 2018
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Ingår i: Journal of Computer-Aided Molecular Design. - : Springer Science and Business Media LLC. - 0920-654X .- 1573-4951. ; 32:10, s. 1027-1046
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Tidskriftsartikel (refereegranskat)abstract
- We have estimated free energies for the binding of eight carboxylate ligands to two variants of the octa-acid deep-cavity host in the SAMPL6 blind-test challenge (with or without endo methyl groups on the four upper-rim benzoate groups, OAM and OAH, respectively). We employed free-energy perturbation (FEP) for relative binding energies at the molecular mechanics (MM) and the combined quantum mechanical (QM) and MM (QM/MM) levels, the latter obtained with the reference-potential approach with QM/MM sampling for the MM → QM/MM FEP. The semiempirical QM method PM6-DH+ was employed for the ligand in the latter calculations. Moreover, binding free energies were also estimated from QM/MM optimised structures, combined with COSMO-RS estimates of the solvation energy and thermostatistical corrections from MM frequencies. They were performed at the PM6-DH+ level of theory with the full host and guest molecule in the QM system (and also four water molecules in the geometry optimisations) for 10–20 snapshots from molecular dynamics simulations of the complex. Finally, the structure with the lowest free energy was recalculated using the dispersion-corrected density-functional theory method TPSS-D3, for both the structure and the energy. The two FEP approaches gave similar results (PM6-DH+/MM slightly better for OAM), which were among the five submissions with the best performance in the challenge and gave the best results without any fit to data from the SAMPL5 challenge, with mean absolute deviations (MAD) of 2.4–5.2 kJ/mol and a correlation coefficient (R2) of 0.77–0.93. This is the first time QM/MM approaches give binding free energies that are competitive to those obtained with MM for the octa-acid host. The QM/MM-optimised structures gave somewhat worse performance (MAD = 3–8 kJ/mol and R2 = 0.1–0.9), but the results were improved compared to previous studies of this system with similar methods.
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| 2. |
- Wang, Meiting, et al.
(författare)
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Convergence criteria for single-step free-energy calculations : the relation between the Π bias measure and the sample variance
- 2024
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Ingår i: Chemical Science. - 2041-6520.
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Tidskriftsartikel (refereegranskat)abstract
- Free energy calculations play a crucial role in simulating chemical processes, enzymatic reactions, and drug design. However, assessing the reliability and convergence of these calculations remains a challenge. This study focuses on single-step free-energy calculations using thermodynamic perturbation. It explores how the sample distributions influence the estimated results and evaluates the reliability of various convergence criteria, including Kofke's bias measure Π and the standard deviation of the energy difference ΔU, σΔU. The findings reveal that for Gaussian distributions, there is a straightforward relationship between Π and σΔU, free energies can be accurately approximated using a second-order cumulant expansion, and reliable results are attainable for σΔU up to 25 kcal mol−1. However, interpreting non-Gaussian distributions is more complex. If the distribution is skewed towards more positive values than a Gaussian, converging the free energy becomes easier, rendering standard convergence criteria overly stringent. Conversely, distributions that are skewed towards more negative values than a Gaussian present greater challenges in achieving convergence, making standard criteria unreliable. We propose a practical approach to assess the convergence of estimated free energies.
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| 3. |
- Wang, Meiting, et al.
(författare)
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Host-Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations
- 2019
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 15:4, s. 2659-2671
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Tidskriftsartikel (refereegranskat)abstract
- Relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host were calculated at the combined density-functional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 6-31G∗ basis set for the ligand. We employed free-energy perturbations (FEP) with the reference-potential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6-DH+ method for the ligand as an intermediate level between MM and DFT/MM to improve the convergence. Thus, the relative binding free energy of two ligands was first calculated at the MM level by an alchemical transformation from one ligand to another in both the bound and unbound states. Then, for each ligand the free-energy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the free-energy correction for going from the SQM/MM to the DFT/MM potentials was estimated with FEP without running any DFT/MM simulations. Instead, the free energy was calculated by single-step exponential averaging (ssEA) or employing the cumulant approximation to the second order (CA). The results show that CA converges much better than ssEA, and with 500-4500 DFT/MM single-point energy calculations, converged free energies with a precision of 0.3 kJ/mol can be obtained. These free energies reproduce the experimental binding free energy differences with a mean absolute deviation of 3.4 kJ/mol, a correlation (R 2 ) of 0.97, and correct signs for all of the eight free-energy differences. This is appreciably better than the results obtained at the SQM/MM level of theory and also slightly better than those obtained with MM. We show that the convergence of the SQM/MM → DFT/MM perturbations can be monitored by the use of Wu and Kofke's bias metric and by the standard deviation of the difference between the SQM/MM and DFT/MM energies. Finally, we show that the use of the intermediate SQM/MM MD simulations improves the convergence of the free energies by a factor of at least two, compared to doing direct MM → DFT/MM perturbations.
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| 4. |
- Wang, Meiting, et al.
(författare)
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Predicting Relative Binding Affinity Using Nonequilibrium QM/MM Simulations
- 2018
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Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 14, s. 6613-6613
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Tidskriftsartikel (refereegranskat)abstract
- Calculating binding free energies with quan-tum-mechanical (QM) methods is notoriously time-consum-ing. In this work, we studied whether such calculations can beaccelerated by using nonequilibrium (NE) moleculardynamics simulations employing Jarzynski’s equality. Westudied the binding of nine cyclic carboxylate ligands to theocta-acid deep-cavity host from the SAMPL4 challenge withthe reference potential approach. The binding free energieswere first calculated at the molecular mechanics (MM) levelwith free energy perturbation using the generalized Amberforce field with restrained electrostatic potential charges forthe host and the ligands. Then the free energy corrections for going from the MM Hamiltonian to a hybrid QM/MM Hamiltonian were estimated by averaging over many short NE molecular dynamics simulations. In the QM/MM calculations, the ligand was described at the semiempirical PM6-DH+ level. We show that this approach yields MM → QM/MM free energy corrections that agree with those from other approaches within statistical uncertainties. The desired precision can be obtained by running a proper number of independent NE simulations. For the systems studied in this work, a total simulation length of 20 ps was appropriate for most of the ligands, and 36−324 simulations were necessary in order to reach a precision of 0.3 kJ/ mol.
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| 5. |
- Xu, Yongtao, et al.
(författare)
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Design Two Novel Tetrahydroquinoline Derivatives against Anticancer Target LSD1 with 3D-QSAR Model and Molecular Simulation
- 2022
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Ingår i: Molecules. - : MDPI AG. - 1420-3049. ; 27:23
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Tidskriftsartikel (refereegranskat)abstract
- Lysine-specific demethylase 1 (LSD1) is a histone-modifying enzyme, which is a significant target for anticancer drug research. In this work, 40 reported tetrahydroquinoline-derivative inhibitors targeting LSD1 were studied to establish the three-dimensional quantitative structure–activity relationship (3D-QSAR). The established models CoMFA (Comparative Molecular Field Analysis (q2 = 0.778, (Formula presented.) = 0.709)) and CoMSIA (Comparative Molecular Similarity Index Analysis (q2 = 0.764, (Formula presented.) = 0.713)) yielded good statistical and predictive properties. Based on the corresponding contour maps, seven novel tetrahydroquinoline derivatives were designed. For more information, three of the compounds (D1, D4, and Z17) and the template molecule 18x were explored with molecular dynamics simulations, binding free energy calculations by MM/PBSA method as well as the ADME (absorption, distribution, metabolism, and excretion) prediction. The results suggested that D1, D4, and Z17 performed better than template molecule 18x due to the introduction of the amino and hydrophobic groups, especially for the D1 and D4, which will provide guidance for the design of LSD1 inhibitors.
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