at each stage. After equilibration, we ran 1 microsecond (µs) using molecular dynamics (MD) and 600 nanoseconds (ns) to 1 microsecond using BLUES for each pose selected by our MDS-RMSD filtering protocol (described in the previous section). We note that some BLUES simulations were run less than 1 microsecond due to limitations in our available compute resources. Our simulations were run using 4 femtosecond (fs) timesteps and with the hydrogen-mass repartioning scheme. Briefly, we describe our protocol for BLUES simulations. A BLUES simulation begins with the NCMC phase, which involves proposing a random rotation about the ligand center of mass and then relaxes via a series of non-equilibrium switching steps which alchemically scale the ligand interations off/on over N steps. This is in contrast to traditional Monte Carlo, which involves performing an instantaneous change to the ligand coordinates. Specifically, interactions are controlled via a parameter (λ 0→1 ) which scales the ligand interactions with the surrounding environment. Our non-equilibrium switching protocol begins with the fully interacting ligand at λ 0 and then we alchemically scale the ligand forces off until λ 0.5 , where the ligand is no longer interacting with surrounding atoms. We perform the proposed random rotation on the non-interacting ligand and then alchemically scale the ligand forces back on until λ 1 , where the ligand is fully interacting and in the proposed position. Over the series of N NCMC switching steps, we accumulate the total non-equilibrium work done and use this in acceptance or rejection of the proposed move (following the Metropolis-Hasting acceptance criterion ). After the Metropolization step, we follow-up using traditional MD methodology and repeat the cycle (NCMC -> MD -> NCMC...etc.) for I iterations.