Binding modes often interconvert slowly compared to the timescales of typical MD simulations, and thus interconversions are not generally observed in free energy calculations unless enhanced sampling techniques are used. As a result, if the binding mode is uncertain or may change as a ligand is modified (e.g. in a lead optimization context) one needs to perform separate free energy calculations starting from each binding mode to compute the total binding free energy. This increases the overall computa-tional cost of binding affinity calculations for ligands with multiple binding modes. However, if the population distribution of binding modes are known, the the binding affinity calculation can become faster and cheaper. Specifically, if we know the probability p 1 of binding mode 1, then total binding free energy G • is given as -