Figure 3.

Calculated free energy profiles for the (A) solvent- and (B) substrate-assisted hydrolysis of GTP in aqueous solution, and as catalyzed by Ras and the RasGAP complex. (C) Activation free energies for each of the two mechanisms, as catalyzed by a range of GTPases (Ras, Rab and G_αι, both with and without their corresponding regulatory proteins, as well as the Ras Q61H mutant). Note that as shown in panel A, the initial phosphoryl transfer reaction in the solvent-assisted hydrolysis of GTP leads to a short-lived intermediate (INT), which will then tautomerize to yield the final product, which is chemically identical to the final product state for the substrate-assisted pathway. A similar pathway was observed in quantum chemical calculations of phosphate esters in aqueous solution.⁸⁻¹⁰ For further details, see ref (7). Reprinted with permission from ref (7) (direct link: https://pubs.acs.org/doi/10.1021/jacs.9b03193). Copyright 2019 American Chemical Society.