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.
Highlights
Estimating the affinity between a small molecule and a biomacromolecule is important in many parts of chemistry, especially in drug design [1, 2]
[3], via end-point approaches, like linear interaction energy [4] and molecular mechanics (MM)/PBSA [5, 6], to strict approaches based on free-energy perturbation (FEP) [7, 8] with free energies calculated by exponential averaging (EA) [9], thermodynamic integration [10] or the Bennett acceptance ratio (BAR) approach [11]
We performed standard relative FEP calculations at the MM level with free energies calculated with multi-state Bennett acceptance-ratio (MBAR) and employing the general AMBER force field (GAFF)+TIP3P force fields and RESP charges
Summary
Estimating the affinity between a small molecule and a biomacromolecule is important in many parts of chemistry, especially in drug design [1, 2]. [3], via end-point approaches, like linear interaction energy [4] and MM/PBSA (molecular mechanics combined with Poisson–Boltzmann and surface area solvation) [5, 6], to strict approaches based on free-energy perturbation (FEP) [7, 8] with free energies calculated by exponential averaging (EA) [9], thermodynamic integration [10] or the Bennett acceptance ratio (BAR) approach [11] The latter methods should in principle be limited only by the accuracy of the potential-energy function and the sampling of the phase space, uncertainties in the nature of the simulated system (e.g. the protonation state of all involved molecules and residues) may affect the results [7, 8]. A few studies have involved sampling at the QM/MM level, typically using a semiempirical QM (SQM) method [19,20,21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
