There are a number of common sampling methods which can be used so that simulations sample the equilibrium distribution of populations. The effi-ciency of these methods can vary dramatically depending on which particular system or class of problem they are applied to, and a method that works best for one class of problem is not necessarily most suitable for another class. Thus it is often nontrivial to determine which sampling method is best suited to a particular problem, or whether there is even a suitable method. Here, our particular interest is in accelerating sampling across ligand binding modes while still sampling the correct distribution of populations. Our goal is to develop a general method that can efficiently determine binding mode populations, in part by reducing the time it takes for simulations to switch between binding modes relative to other methods. This section will discuss some common sampling methods and the difficulties they encounter when applied to the ligand binding mode sampling problem.