Here we introduce the Flexible Topology method, which allows the topology to change over the course of the simulation by treating the attributes that define atomic identities as dynamic variables. This builds on the idea of "alchemy" in molecular simulation, which has a long history. MD simulations that utilize alchemy to measure relative binding free energies were described as early as 1984. In alchemical simulations, an external parameter, normally denoted by λ , is used to "turn on" or "turn off" additional terms in a potential energy function: U(X, λ ) = U 0 (X) + λU pert (X).