our primary focus is on different "binding modes": defined as different metastable conformations of a fragment-like ligand within a single relatively rigid protein cavity. Metastable binding modes are thus those which are slow to interconvert on a simulation timescale z. Generally, if binding modes interconvert at a timescale slower than z/10 then proper sampling is a major concern; different metastable conformations may have different binding free energies but will be sampled in incorrect proportions, resulting in highly biased results. Moreover, the concept of a binding mode can include multiple ligand conformations in the same site, binding to in multiple sites, or even multiple protein conformations, 1 though we do not specifically address enhanced sampling of protein motion here.