Move proposal biasing however, if applied haphazardly, can disrupt detailed balance, distorting the resulting distribution of states sampled. In order to ensure the reversibility of our move proposals, a biased move is only proposed when the rotamer is in one of the pre-defined favored states, so that move proposals and their corresponding reverse rotations have equivalent probabilities. For the random rotations of ligands in BLUES, the intermixing of NCMC and MD proceeds in an alternating fashion -every m MD steps, an NCMC move is proposed (e.g., NCMC→MD→NCMC→MD). When using BLUES with biased sidechain rotations, however, move proposals may be more irregular. Specifically, after m MD steps, an NCMC move is only proposed if the current rotamer state falls within one of the favored rotamer states, otherwise more another round of m MD steps is executed executed and the process is repeated until the condition is satisfied (eg. MD→NCMC→MD→MD→MD→NCMC→MD Figure .