Host-guest systems are widely used in benchmarks as model systems to improve computational methods for absolute binding free energy predictions. Recent advances in sampling algorithms for alchemical free energy calculations and the increase in computational power have made their binding affinity prediction primarily dependent on the quality of the force field. Here, we propose a new methodology to derive the atomic charges of host-guest systems based on QM/MM calculations and the MBIS partitioning of the polarized electron density. A newly developed interface between the OpenMM and ORCA software package provides D-MBIS charges that best represent the guest’s average electrostatic interactions in the hosts or the solvent. The simulation workflow also calculates the average energy required to polarize the guest in the bound and unbound state. Alchemical free energy calculations using the GAFF force field parameters with D-MBIS charges improve the binding affinity prediction of six guests bound to two octa-acid hosts compared to the AM1-BCC charge set after correction with the average energetic polarization cost. This correction results from the difference in the energetic polarization cost between the bound and unbound state and contributes significantly to the binding affinity of anionic guests.
Minor changes in the introduction and the discussion during the reviewing process.
Supporting host guest SAMPL5 DMBIS