Follow the protons: A low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases

Seven proton transfers in five steps participate in a catalytic turnover of an aspartic protease. The Rosetta Stone for elucidating their role is a low-barrier hydrogen bond that holds the two aspartic carboxyls in a coplanar conformation. The proton of this bond shuttles between oxygens during chemical steps via hydrogen tunneling, unlike in previous proposals where it was transferred to substrate. After the release of products, both carboxyls are protonated and the bond is missing. Re-forming the bond is a significant step within a kinetic isomechanism. The bond also explains-at long last-the extremely low pK in pH profiles.