Buried protein cavities may accommodate water molecules, and it is generally more favorable to fill a polar cavity with water than to leave it unoccupied. Water exchange between bulk and cavities can occur on a very long time scale, depending on the nature of the free energy surface, and exchange can be particularly slow if these cavities are deeply buried. Furthermore, large conformational changes may be required to allow the water to exchange with the bulk. Standard molecular dynamics (MD) simulations, which integrate Newton's equations of motion, are computationally demanding and can require a very long time to account for large conformational changes, adding to the challenge of efficiently sampling water exchange in buried cavities. Thus, a conformational ensemble from MD that does not efficiently sample the exchange of water between bulk and buried cavities may not be with concordance with the proper Boltzmann distribution associated with the conditions (e.g., solvent composition and temperature) of the simulation. Moreover, a simulation might appear to be converged, while in reality it is stuck in a local minimum and unable to sample important states for the buried water molecules.