posted on 2021-08-31, 18:33authored byDuván González, Luis Macaya, Esteban Vöhringer-Martinez
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 quantum
mechanics/molecular mechanics calculations and minimal basis iterative
stockholder (MBIS) partitioning of the polarized electron density.
A newly developed interface between the OpenMM and ORCA software packages
provides D-MBIS charges that 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 general Amber 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 originates
from the difference in potential energy that is required to polarize
the guest in the bound and unbound state and contributes significantly
to the binding affinity of anionic guests.