In this study, we used two simulation approaches: traditional molecular dynamics (MD) simulations and our hybrid approach called BLUES: Binding modes of Ligands Using Enhanced Sampling, which combines Non-equilibrium Candidate Monte Carlo (NCMC) move proposals with MD. Both MD and BLUES simulations using OpenMM (v7.1.1) 43 with the same solvated SEH system. For our simulations, the truncated SEH protein (consisting of only the C-terminal domain) was paramterized with amber99sbildn forcefield for the protein and GAFF2 for the ligands, and solvated with TIP3P waters. We performed a maximum of 30,000 energy minimization steps and a 3 stage (NVT, NPT, NPT) equilibration protocol which we describe as follows. In each equilibration stage, a restraint force is placed on the α-Carbons of the protein backbone and the ligand heavy atoms, where we successively decrease the force from 2.0 kcal mol•Å