Methodological and force field effects in the molecular dynamics-based prediction of binding free energies of host–guest systems

As a contribution to the understanding and rationalization of methodological and modeling effects in recent host-guest SAMPL challenges, using an alchemical molecular dynamics technique we have examined the impact of force field parameterization and ionic strength in connection with guest charge neutralization on computed dissociation free energies in two typical SAMPL heavily charged macrocyclic hosts encapsulating small protonated amines with disparate binding affinities. We have shown that the methodological treatment for host neutralization, with explicit ions or with the background neutralizing plasma in the context of alchemical calculations under periodic boundary conditions, has a moderate effect on the calculated affinities. On the other hand, we have shown that seemingly small differences in the force field parameterization in highly symmetric hosts can produce systematic effects on the structural features that can have a significant impact on the predicted binding affinities.