Impacts of Mutations in the P-Loop on Conformational Alterations of KRAS Investigated with Gaussian Accelerated Molecular Dynamics Simulations.

ABSTRACT: G12 mutations heavily affect conformational transformation and activity of KRAS. In this study, Gaussian accelerated molecular dynamics (GaMD) simulations were performed on the GDP-bound wild-type (WT), G12A, G12D, and G12R KRAS to probe mutation-mediated impacts on conformational alterations of KRAS. The results indicate that three G12 mutations obviously affect the structural flexibility and internal dynamics of the switch domains. The analyses of the free energy landscapes (FELs) suggest that three G12 mutations induce more conformational states of KRAS and lead to more disordered switch domains. The principal component analysis shows that three G12 mutations change concerted motions and dynamics behavior of the switch domains. The switch domains mostly overlap with the binding region o

SUBMITTER: Shi S 

PROVIDER: S-EPMC10095679 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature