FIG. 4.

Reference configurations chosen for restraints. From the unrestrained simulations initiated from the three orientations obtained by clustering DOCK poses, we identify two orientations [(a) and (b)] between which sampling is slow compared to 1 ns. Separate free energy calculations are conducted using each of these as a reference orientation for restraint. The final snapshots from the molecular dynamics trajectories run with full-strength restraints on the ligand are shown.