Thermodynamic Integration is a standard technique, which is briefly described below for completeness. MD TI BFE simulations are designed to compute the relative free energy of two molecular systems by transforming one molecular system into another by performing multiple stratified equilibrium MD simulations along a pre-defined reaction coordinate, i.e. an alchemical thermodynamic pathway. Typically, the pathway is defined as a linear interpolation between the Hamiltonians of two systems A and B: