LAUSR

Calculation of binding free energies, which characterize the stability and specificity of molecular interactions (e.g., drug formulations), has been established as an important application of modern computational chemistry. Though several methodologies currently exist within the literature, there is always a need for improvements in speed an accuracy that allow for more efficient chemical screening. In this paper we explore the application of an unrestrained advanced sampling method, adaptive biasing force (ABF), to the calculation of standard binding free energies for a set of molecular host-guest systems for which the binding free energy is well known: the cucurbit[7]uril-hosted systems utilized in the HYDROPHOBE challenge [Assaf, et al, J. Phys. Chem. B, 121, 11144-11162 (2017)]. We demonstrate that the use of the ABF advanced sampling method yields values systematically closer to experiment, with a lower uncertainty in the calculation, than various restraint-based calculations while simultaneously requiring less simulation time. These results show the promise of unrestrained advanced sampling methods along well-defined reaction coordinates in the calculation of binding energies in host-guest systems.