Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with aromatic or adamantane core and the CB7 host using molecular electron density derived non-bonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the minimal basis iterative stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound state. The resulting non-bonded force field parameters improve binding affinity prediction, especially for guests with adamantane core in which repulsive exchange and dispersion interactions to the host dominate.
Figure S1-S6 show the conformations adopted by guests BG1-BG6 and Tables S1-S6 the probability to find these conformations together with the number of frames in which water molecules were found in the host. Figure S7 displays the different conformations adopted by guests with adamantane core and Table S7-S10 the probability to observe these conformations using the RESP/AM1-BCC atomic charges for host and guest or the D-MBIS atomic charges for both and finally replacing the Lennard-Jones parameters from GAFF with the ones derived with D-MBIS. Figure S8 presents the SAPT analysis for the interaction of the AG8 guest with the CB7 host. Figure S9 displays the radial distribution function of the water oxygen atoms with the center of mass of the AG7 and AG1 guest with the different combination of atomic charges and LJ parameters.