Why Does the Ras Switch "Break" by Oncogenic Mutations?

The elucidation of the structure of the RasGAP complex provides what is perhaps the most detailed link between protein structure and cancer causing mutations. In particular, it is known that mutations of Gln 61 destroy the GTPase activity of the complex, locks the cell in its ON state and thus, can cause cancer. It is entirely unclear however, why this specific mutation is so important. The present work uncovers the elusive role of Gln 61 by computer simulation of the GTPase reaction in Ras, RasGAP and of their mutants. Simulations of the effects of mutations of Gln 61 reproduce the corresponding observed changes in activation energies and allow us to analyze the energy contributions to these effects. It is found that Gln 61 does not operate in a direct chemical way nor by a direct electrostatic or steric interaction with the transition state (TS). Instead, oncogenic mutations of Gln 61 lead to the destruction of the exquisitely preorganized catalytic configuration of the active site of the RasGAP complex. This "allosteric" effect causes a major reduction in the electrostatic stabilization of the TS. Our findings have general relevance to other proteins that control signal transduction processes.