Ras Structure, Dynamics and Conformational States Assessed by MD Simulations and Solution Wide angle X-ray Scattering

Ras is a small GTPase that is involved in up to 30% of cancers. A wealth of evidence suggests that despite high sequence similarity of the Ras isoforms, H‐Ras, K‐Ras, and N‐Ras, there are distinct differences in signaling, localization, mutation position, and outcomes in cancer. Even in the absence of the C‐terminal hypervariable region (HVR), there are differences between the isoforms in the rates of GTP hydrolysis and in the details of Ras structure and dynamics. Here we present accelerated molecular dynamics simulations paired with solution x‐ray scattering that reveal differences in the conformational sampling of H‐Ras, K‐Ras4B, and N‐Ras. Specific interactions within water‐mediated allosteric networks are altered by the presence of isoform specific residues that impact accessibility to the catalytic state. Thus, the isoforms sample the same main three conformational states, but the population of each one is shifted by changes driven by isoform‐specific residues that may be associated with fine‐tuning preferences for signaling through distinct pathways and susceptibility to specific mutations observed in cancers. Support or Funding Information NSF MCB‐1517295