In the above production simulations of CF-SMD and unbiased MD, the temperature was controlled using the Langevin thermostat 37 with a time constant of 2.0 ps; the time step was set to 2.0 fs; non-bonded interactions were cut off at 10 Å. Electrostatic interactions were computed using the particle-mesh Ewald method , and bonds with hydrogen atoms were constrained using LINCS .