We recently developed a method that combines replica exchange with metadynamics and allows, with a moderate computational effort, the simultaneous reconstruction of the free energy as a function of a large number of variables. This allows simulating very complex reactions, like protein folding, in which the reaction coordinate is totally unknown. We will discuss applications of the methodology to the folding in explicit solvent of the TRP cage miniprotein and of the advillin headpiece C-terminal domain (cHP) and its Pro62Ala mutant. Our calculations allow, for these small proteins, the ab initio prediction of the folded state. For the advillin headpiece we find that the Pro62Ala mutation does not change the overall stability of the native state but it significantly alters the entropic contribution to the folding free energy. Therefore, the mutant is still folded at room temperature but is characterized by a lower unfolding temperature. This prediction was subsequently validated by NMR and CD experiments.