Investigating the effects of cysteine-118 oxidation on G12D KRas structure and dynamics: insights from MD simulations.

Mutations of Ras proteins are believed to be among the most prominent causes of cancer. There is increasing evidence that the activity of Ras may be controlled by the redox state of cysteine residues located within the NKCD motif. This redox signaling is critical to both physiological and pathological processes and occurs when C118 is oxidized in a reversible manner. In this study, we used atomistic molecular dynamics simulations and Markov state models to investigate the structural and conformational effects of C118 oxidation on the oncogenic mutant KRas(G12D). While both mutants share common features and exhibit some distinct conformational states and fluctuations, we have found that the oxidized variant KRas(G12D/C118SOH) is more dynamic than the unoxidized counterpart, particularly in the switch II region. Additionally, C118 oxidation is found to alter the structure of the nucleotide-binding site and the switch regions as well as perturb the conformational equilibrium between Ras active and inactive states. These conformational preferences may alter the affinity to different effectors, resulting in selective downstream activation. Our results are anticipated to help future drug development efforts aimed at KRAS-related anticancer treatment.Communicated by Ramaswamy H. Sarma.