Use of the Grand Canonical Ensemble in Potential of Mean Force Calculations Abstract: Understanding and predicting the thermodynamics of association reactions at the microscopic level requires that it be possible to sample representative configurations of the reactants and solvent as a function of the reaction pathways. Because of geometrical effects, certain methodological improvements in molecular simulation techniques are necessary before the reaction thermodynamics of complicated systems such as biopolymers with interlocking shapes can be investigated. Here, we propose the use of the grand canonical ensemble in molecular simulations when the traditional canonical ensemble based methods cannot appropriately account for the confined space effects. The success of the grand canonical ensemble molecular simulations in studying the association reaction profile is shown by testing it on simpler systems. Implications for future work and various possible application areas of the grand canonical ensemble simulations are discussed.