Sidechain BLUES enhances sampling of sidechain rotamer states, as compared with classical MD, for systems where there is an existing (or artificially inflated) high torsional barrier. Here we have demonstrated an increase in sampling efficiency for both our valine-alanine dipetide as well as our larger T4 lysozyme/p-xylene system which has known sidechain sampling problems, and this improved sampling has the potential to improve binding free energy calculations. However, in the case of the T4 lysozyme/p-xylene system studied here, without long exploratory classical simulations, alternate backbone configurations could be missed; in classical MD, these appear to essentially lock the relevant sidechain in a single rotameric state by increasing the transi-tion barrier, whereas with BLUES, transitions are still possible. Nonetheless, the BLUES framework readily allows for integration of various move types and in the future, sidechain sampling could be combined with enhanced backbone sampling. In this work, application of sidechain BLUES has been limited to sampling of a single valine sidechain, but the method has been implemented such that it can readily be applied to other amino acid residues. Currently, BLUES with sidechain rotations can be used to sample multiple sidechain rotamers by randomly and sequentially applying the NCMC procedure to rotamers within residues in a list of user specified residues (Figure ). Given the flexibility of its implementation, BLUES can be used to explore and more readily identify residues in a protein binding site that are most likely to undergo some sort of conformational reformation, and sample such rearrangements much more efficiently than MD. It can also be mixed with different BLUES move types (some established and some in development) such as ligand flips and internal bond rotations, ligand translocations, and water translocations.