Free Energy Profiles Relating With Conformational Transition of the Switch Domains Induced by G12 Mutations in GTP-Bound KRAS.

Mutations of G12 in KRAS have been involved in different cancers. Multiple replica-Gaussian accelerated molecular dynamics (MR-GaMD) simulations are applied to investigate conformational changes of the switch domains caused by G12C, G12D and G12R. Free energy landscapes suggest that G12C, G12D and G12R induce more energetic states compared to the GTP-bound WT KRAS and make the conformations of the switch domains more disordered, which disturbs bindings of KRAS to effectors. Dynamics analyses based on MR-GaMD trajectory show that G12C, G12D and G12R not only change structural flexibility of the switch domains but also affect their motion behavior, indicating that these three mutations can be used to tune the activity of KRAS. The analyses of interaction networks verify that the instability in interactions of the GTP with the switch SⅠ plays an important role in the high disorder states of the switch domain. This work is expected to provide useful information for deeply understanding the function of KRAS.