The msesMD trajectories yield free energy profiles along  F , the torsion angle most diagnostic of open and closed conformations, in closer accord with the profile from triplicate 10 s simulations than that calculated via umbrella sampling. The latter appears to experience limited sampling due to the 20 ns windows employed. Furthermore, msesMD simulations identify a new G 5 well for sLe a which is absent from the triplicate 10 s simulations, but features in aMD simulations of sLe a and unbiased MD calculations of Le a (Figures and). Differences in the stability of sLe a conformers as calculated by unbiased MD and msesMD are found, particularly for the G 4 well, and appear to arise from limited sampling in the unbiased MD simulations.