Key Oncogenic Ras Mutations Impair Limiting Proton Transfer Rates

30 December 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Ras-positive cancer constitutes a major challenge for medical treatment. Hot spot residues Gly12, Gly13 and Gln61 constitute the majority of oncogenic mutations which are associated with detrimental clinical prognosis. Here we present a two-step mechanism of GTP hydrolysis of the wild type Ras.GAP complex using QM/MM free energy calculations with the finite-temperature string method. We found that the deprotonation of the catalytic water takes place via the Gln61 as a transient Brønsted base. We obtained reaction profiles for key oncogenic Ras mutants G12D and G12C, reproducing the experimentally observed loss of catalytic activity, and validating our reaction mechanism.


enhanced sampling
proton transfer

Supplementary materials

Supporting Information
Computational details of the model built and QM/MM calculations, contact analysis of molecular dynamics, natural orbital analysis results, alternative mechanisms, distances and charges calculated for mutant reaction paths.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.