Binding free energies in the SAMPL6 octa-acid host–guest challenge calculated with MM and QM methods

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 (R) 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 R = 0.1-0.9), but the results were improved compared to previous studies of this system with similar methods.

SAMPL6 host–guest binding affinities and binding poses from spherical-coordinates-biased simulations

“…In the 6 th statistical assessment of the modeling (SAMPL6), the host-guest binding is one of the main challenge and many researchers submitted predictions obtained from various simulation techniques. 71,[74][75] For instance, equilibrium free energy simulation methods such as umbrella sampling and the double decoupling method were used to calculate the binding affinities. 70,73 The nonequilibrium pulling technique in the alchemical space was employed to obtain the binding affinities.…”

SAMPL7 TrimerTrip host–guest binding poses and binding affinities from spherical-coordinates-biased simulations

“…Therefore, they serve as nice candidates for calibrating computational approaches. 96,[99][100][101] Due to the similarity between host-guest systems and protein-ligand complexes, similar free energy methods are employed to investigate the host-guest binding. For instance, equilibrium free energy methods such as umbrella sampling and the double decoupling method were used to calculate the binding free energies in the SAMPL6 host-guest cases.…”

SAMPL7 TrimerTrip Host-Guest Binding Poses and Binding Affinities from Spherical-Coordinates-Biased Simulations

“…Therefore, they serve as nice candidates for calibrating computational approaches. 93,[96][97][98] Due to the similarity between host-guest systems and protein-ligand complexes, similar free energy methods are employed to investigate the host-guest binding. For instance, equilibrium free energy methods such as umbrella sampling and the double decoupling method were used to calculate the binding free energies in the SAMPL6 host-guest cases.…”