Conformational and Dynamical Effects of Tyr32 Phosphorylation in K-Ras: Molecular Dynamics Simulation and Markov State Models Analysis.

ABSTRACT: Phosphorylation of tyrosine 32 in K-Ras has been shown to influence function by disrupting the GTPase cycle. To shed light on the underlying mechanism and atomic basis of this process, we carried out a comparative investigation of the oncogenic G12D K-Ras mutant and its phosphorylated variant (pTyr32) using all-atom molecular dynamics simulations and Markov state models. We show that, despite sharing a number of common features, G12D and pTyr32-G12D K-Ras exhibit some distinct conformational states and fluctuations. In addition to notable differences in conformation and dynamics of residues surrounding the GTP binding site, nonlocal changes were observed at a number of loops. Switch I is more flexible in pTyr32-G12D K-Ras while switch II is more flexible in G12D K-Ras. We also used time-la

SUBMITTER: Khaled M 

PROVIDER: S-EPMC7020251 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature