HostGuest Relative Binding Affinities at DensityFunctional Theory Level from Semiempirical Molecular Dynamics Simulations
(2019) In Journal of Chemical Theory and Computation Abstract
Relative free energies for the binding of nine cyclic carboxylate ligands to the octaacid deepcavity host were calculated at the combined densityfunctional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 631G∗ basis set for the ligand. We employed freeenergy perturbations (FEP) with the referencepotential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6DH+ 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... (More)
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Relative free energies for the binding of nine cyclic carboxylate ligands to the octaacid deepcavity host were calculated at the combined densityfunctional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 631G∗ basis set for the ligand. We employed freeenergy perturbations (FEP) with the referencepotential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6DH+ 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 freeenergy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the freeenergy 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 singlestep 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 5004500 DFT/MM singlepoint 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 freeenergy 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.
 author
 Wang, Meiting; Mei, Ye and Ryde, Ulf ^{LU}
 organization
 publishing date
 2019
 type
 Contribution to journal
 publication status
 epub
 subject
 in
 Journal of Chemical Theory and Computation
 publisher
 The American Chemical Society
 external identifiers

 scopus:85063157420
 ISSN
 15499618
 DOI
 10.1021/acs.jctc.8b01280
 language
 English
 LU publication?
 yes
 id
 403c1ce9da224531a4e4dad937de9f77
 date added to LUP
 20190408 13:51:33
 date last changed
 20190423 04:49:11
@article{403c1ce9da224531a4e4dad937de9f77, abstract = {<p><br> Relative free energies for the binding of nine cyclic carboxylate ligands to the octaacid deepcavity host were calculated at the combined densityfunctional theory and molecular mechanics (DFT/MM) level of theory. The DFT calculations employed the BLYP functional and the 631G∗ basis set for the ligand. We employed freeenergy perturbations (FEP) with the referencepotential approach and used molecular dynamics (MD) simulations with the semiempirical quantum mechanical (SQM) PM6DH+ 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 freeenergy correction for going from the MM to the SQM/MM potentials was calculated using explicit SQM/MM MD simulations. Finally, the freeenergy 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 singlestep 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 5004500 DFT/MM singlepoint 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 <br> <sup>2</sup><br> ) of 0.97, and correct signs for all of the eight freeenergy 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. <br> </p>}, author = {Wang, Meiting and Mei, Ye and Ryde, Ulf}, issn = {15499618}, language = {eng}, publisher = {The American Chemical Society}, series = {Journal of Chemical Theory and Computation}, title = {HostGuest Relative Binding Affinities at DensityFunctional Theory Level from Semiempirical Molecular Dynamics Simulations}, url = {http://dx.doi.org/10.1021/acs.jctc.8b01280}, year = {2019}, }