One of the most important problems facing free energy calculations by computer simulations for complex systems such as proteins and nucleic acids is the need to enhance the search of their configurational space. One characteristic of such systems is a broad range of energy barriers at many scales, both lower and higher than the thermal energy. The ergodic hypothesis [1] relies on the assumption that equilibrium time averages are equal to the corresponding thermodynamic ensemble averages. As a consequence, every point in the phase space must be accessible from every other point.