For systems 4 and 5, again following the original works, we used force constants of 4184 kJ/mol/nm 2 = 10 kcal/mol/Å 2 and 1000 kJ/mol/nm 2 , respectively. The lengths of umbrella sampling simulations for systems 1, 2, 4, and 5 were 10 ns per US window in each repeat, resulting in a total of 200-300 ns per system. For system 4, simulating 10 ns per window was ten times longer than in the original work, and for system 5, the same as in the original work. For system 3, each umbrella window was simulated for 50 ns.