The interplay of the intramolecular, or internal, energy of a molecule and the non-bonded energetics that determine its interactions with its environment play a crucial role in simulations of protein folding, crystal structure prediction, protein-ligand binding, 5 and many more. In particular, oral drugs are typically flexible, containing on average 5.4 rotatable bonds, and are therefore capable of populating many free energy minima both in solution and also when bound to their target. Computational analysis has revealed that the majority of ligands bind in a conformation within 0.5 kcal mol -1 of a local energy minimum. To be successful, docking or any other method used in computer-aided structure-based drug design must be able to accurately predict both the bioactive conformation of the molecule and the free energy change that accompanies its binding from solution.