The conformation of a catalytic loop is central to GTPase activity on the ribosome.

The translational GTPases hydrolyze GTP on the ribosome at several stages of the protein synthesis cycle. Because of the strong conservation of their catalytic center, these enzymes are expected to operate through a universal hydrolysis mechanism, in which a critical histidine residue together with the sarcin-ricin loop of the large ribosomal subunit is necessary for GTPase activation. Here we examine different possible pathways for GTP hydrolysis by EF-Tu through extensive computer simulations. We show that a conformational change of the peptide plane preceding this histidine has a decisive effect on the energetics of the reaction. This transition was predicted earlier by us and has recently been confirmed experimentally. It is found to promote early proton transfer from water to the γ-phosphate group of GTP, followed by nucleophilic attack by hydroxide ion. The calculated reaction energetics is in good agreement with available kinetic data, for both wild-type and mutant versions of EF-Tu, and indicates that the latter may enforce a change in mechanism toward more concerted pathways.