Successfully predicting binding affinity depends on many factors, including the determination of the most favorable or relevant binding mode, or modes, of the ligand. Medicinal chemists often use knowl-edge of the likely binding mode or binding modes to attempt rational improvements upon the scaffold, as well as giving insight into the important interactions driving binding. The binding mode or binding modes also provide a fundamental input for many calculations that can predict binding affinities, such as free energy calculations. As important as binding modes are, actually determining them can be difficult. The standard experimental techniques for binding mode determination, X-ray crystallography and nuclear magnetic resonance, can be time-consuming, difficult, or costly, and are not suitable for all targets (membrane proteins can be particularly challenging, for instance). Additionally, experimental methods do not always clearly resolve the binding mode. For example, in the case of fragment-based drug discovery, small, relatively rigid ligands can often have some ambiguity in their binding modes because of internal pseudosymmetry, or other issues. Additionally, methods to make X-ray diffraction data easier to collectsuch as cryocooling crystals-potentially stabilize binding modes that are not observed under the conditions of interest. Multiple binding modes may also contribute substantially to a ligand's affinity, therefore knowledge of a single experimental binding mode may be misleading or provide an incomplete picture.