Abstract: The biological function of the homodimeric retropepsin HIV-1 Aspartic protease has recently been related to the conformational flexibility of its structural scaffold. Here we address the fundamental issue on whether such mechanism is present also in the other known fold of aspartic proteases, that is the asymmetric monomeric fold typical of the eukariotic isoenzymes (pepsins). We investigate the mechanisms governing the enzymatic activity of a typical member of the pepsin family, human $\beta$-secretase, through classical MD and hybrid Car-Parrinello MD simulations. As for the viral isoenzyme, the reaction free energy is found to be strongly modulated by a set of large-scale conformational fluctuations of the protein. By using a suitable coarse-grained scheme and multiple sequence alignment techniques we learn that the mechanical response of all members of the pepsin family is analogous to the $\beta$-secretase one. In particular, we find that the conserved residues identify three regions of the protein, located around the cleavage-site cavity, in the four $\beta$-sheets cross-linking the two lobes, and in a solvent-exposede region below the long $\beta$-hairpin in the N-terminal lobe. Residuese in these sets play specific roles in the mechanical properties of the enzyme and yet are very little mobile. The ubiquity of these features in all analyzed structures suggest that aspartic proteases have been evolutionary selected to possess similar functional motions which, in turn, preserve the enzymatic activity mechanisms despite the observed fold variations.