The mean energies of the ligand-protein complexes converge relatively slowly, even in relation to the present simulation times of about 300 µs for each complex, as detailed in Table . Thus, for the separate A and B runs, autocorrelation analysis yields SEM estimates of 0.4 to 3.0 kcal/mol, and none of the blocking curves of the individual runs show consistent plateaus (Panels a and c in Figures and). Additionally, the SEM estimates for the merged A and B runs range from 0.4 to 1.8 kcal/mol (Supporting Information Table ), and blocking analysis of the merged runs still do not show consistent plateaus (Supporting Information Figures ). The uncertainties of these mean energies are about an order of magnitude greater than those for the free ligands, even though the simulations are nearly ten-fold longer.