Host-Guest Relative Binding Affinities at Density-Functional Theory Level from Semiempirical Molecular Dynamics Simulations

Journal of Chemical Theory and Computation
Meiting WangUlf Ryde

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 C...Continue Reading

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Citations

Aug 6, 2020·The Journal of Chemical Physics·Shingo Ito, Qiang Cui
Feb 24, 2020·Current Opinion in Structural Biology·Anita de Ruiter, Chris Oostenbrink
Jun 28, 2019·The Journal of Physical Chemistry Letters·GiovanniMaria Piccini, Michele Parrinello
Sep 17, 2020·Journal of Chemical Information and Modeling·Tai-Sung LeeDarrin M York
Jan 18, 2020·Journal of Chemical Theory and Computation·Christoph Brunken, Markus Reiher
Sep 24, 2021·The Journal of Physical Chemistry Letters·Andrea RizziMichele Parrinello

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