Water distribution within wild type NRas protein and Q61 mutants during unrestrained QM/MM dynamics

Point mutations in p21rasare associated with approximately 30% of human tumors by disrupting its GTP hydrolysis cycle, which is critical to its molecular switch function in cellular signalling pathways. In this work, we investigate the impact of Gln 61 substitutions in the structure of p21N-rasactive site and particularly focus on water reorganization around GTP, which appears to be crucial to evaluate favorable and unfavorable hydration sites for hydrolysis. The NRas-GTP complex is analyzed using hybrid quantum mechanics / molecular mechanics approach treating for the first time to our knowledge transient water molecules at the ab-initio level and leading to results that account for the electrostatic coupling between the protein complex and the solvent.

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