K-Ras is one of the most frequently mutated oncogenes in human tumor cells. It consists
of a well-conserved globular catalytic domain and a flexible tail-like hypervariable
region (HVR) at its C-terminal end. It plays a key role in signaling networks in proliferation,
differentiation, and survival, undergoing a conformational switch between the active
and inactive states. It is regulated through the GDP-GTP cycle of the inactive GDP-bound
and active GTP-bound states. Here, without imposing any prior constraints, we mapped
the interaction pattern between the catalytic domain and the HVR using Molecular Dynamics
with excited Normal Modes (MDeNM) starting from an initially extended HVR conformation
for both states. Our sampling captured similar interaction patterns in both GDP- and
GTP-bound states with shifted populations depending on the bound nucleotide. In the
GDP-bound state, the conformations where the HVR interacts with the effector lobe
are more populated than in the GTP-bound state, forming a buried thus autoinhibited
catalytic site; in the GTP-bound state conformations where the HVR interacts with
the allosteric lobe are more populated, overlapping the alpha 3/alpha 4 dimerization
interface. The interaction of the GTP with Switch I and Switch II is stronger than
that of the GDP in line with a decrease in the fluctuation upon GTP binding.
