Specifically, umbrella sampling is challenging to apply to larger systems because of practical considerations arising from the difficulty of biasing more than one or two degrees of freedom at a time; even application to sample rearrangement of some sidechain rotamers quickly becomes intractable. Imagine umbrella sampling an arginine sidechain where we need to sample the rotation of multiple torsions simultaneously; this would require construction of a multidimensional PMF which, while tractable, involves substantial computational cost. The situation would be further complicated if the arginine neighbored another residue that we also needed to umbrella sample. Furthermore, integrating with other types of simulations would be laborious -for example, a simulation which sampled across ligand binding modes might need a separate umbrella sampling study and associated PMF for each binding mode.