Role of the arginine finger in Ras·RasGAP revealed by QM/MM calculations

In the Ras·RasGAP complex, hydrolysis of guanosine triphosphate is strongly accelerated GAP as compared to Ras alone. This is largely attributed to the arginine finger R789GAP pointing to AlFx in the transition state analogue. We performed QM/MM simulations where triphosphate was treated using the quantum mechanical method of density functional theory, while the protein complex and water environment were described classically using MD. Compared to Ras, the crucial electron shift, bond stretching and distortion towards an eclipsed γ-to-β orientation are much more pronounced. The arginine finger is shown to act by displacing water out of the binding niche. The resulting enhanced electrostatic field catalyses the cleavage step.