Revealing conformational changes of GTP-bound NRAS mutants probed by GaMD and Markov state models

The RAS family proteins, including NRAS, are key regulators of intracellular signaling, acting as molecular switches that control essential cellular processes including proliferation and survival. Oncogenic NRAS mutations exert distinct effects on protein function. We employed Gaussian accelerated molecular dynamics simulations and Markov state models, complemented by principal component analysis and correlation network analysis, to delineate the comprehensive conformational landscapes of GTP-bound wild-type NRAS and its oncogenic G12D, Q61R, and C118S mutants. Our findings reveal that these mutations significantly alter the structural dynamics of the switch I and switch II domains. The Q61R mutation tends to stabilize the overall NRAS conformation. Furthermore, mutations induce specific changes in the protein's internal communication networks. These insights into the dynamic properties of oncogenic NRAS mutants provide a robust mechanistic foundation for understanding aberrant signaling and guiding the rational design of novel anti-cancer therapeutics.