with F q = -k B T ln Q q the free energy. We analogously define p(x), Q p , and F p for the potential energy surface U p (x) of the refined ensemble. In an isothermal ensemble at inverse temperature β = 1/(k B T ), the energy of conformation x is given by U q (x) = E q (x), where E q (x) is its potential energy. In an isobaric-isothermal ensemble, U q (x) = E q (x) + pV q (x), where p is the pressure and V (x) is the box volume for conformation x.