Converged Free Energies of Binding in Cucurbit[7]Uril and Octa-Acid Host Systems from Expanded Ensemble Simulations

Molecular containers, such as cucurbit[7]uril and the octa-acid cavitand host, have been used in a wide variety of applications, including selective drug delivery and release, specific molecular capture, and even for use in molecular machines such as nanoscale locks. Due to their ability to bind guests in a highly specific manner over a wide range of binding affinities, these small-molecule hosts are ideal test systems for optimizing and analyzing methods for computing free energies of binding that are also applicable to biologically relevant proteins. To this end, we have performed initially blind free energy calculations to determine the free energies of binding for ligands of both the cucurbit[7]uril and octa-acid hosts. A subset of the selected guest molecules were those included in the SAMPL4 prediction challenge, to which we made submissions for each host. For the expanded ensemble simulations that we have run, we are able to show that our estimates are converged and that the errors in our estimates are due only to the assigned force field parameters. This is confirmed through the use of alternative thermodynamic pathways, simulations of extended length, and analysis of sampled conformations. Our results also demonstrate the benefits of enhanced sampling of multiple local free energy minima imparted by the use of expanded ensemble molecular dynamics.