Deciphering allosteric mechanisms in KRAS activation: insights from GTP-induced conformational dynamics and interaction network reorganization.

ABSTRACT: The conformational dynamics and activation mechanisms of KRAS proteins are of great importance for targeted cancer therapy. However, the detailed molecular mechanics of KRAS activation induced by GTP binding remains unclear. In this study, we systematically investigated how GTP/GDP exchange affects the thermodynamic and kinetic properties of KRAS and explored the activation mechanism using molecular dynamics (MD) simulations, Markov state models (MSMs), and neural relational inference (NRI) models. Our MD simulation results show that GTP binding significantly enhances the conformational flexibility of KRAS, and thus promotes its transition to an active conformation with more open switch I and II regions. MSMs analyses show that KRAS in the GTP-bound state can be transitioned to the active

SUBMITTER: Zhao DR 

PROVIDER: S-EPMC11755325 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature