K-ras belongs to the Ras family of G-proteins that regulate cell proliferation and development. To execute its function, K-ras adopts different conformational states when it is active and inactive. In addition to these two states, it samples many transient intermediate conformations as it makes the transition from one state to the other. Mutations that affect the population of these states can cause cancer or developmental disorder. We analyzed all available Ras crystal structures and conformers derived from a series of independent explicit solvent molecular dynamics (MD) simulations (totaling 1.76 �s) of Q61H variant of K-ras. We found that the protein samples a different region of phase space in the presence and absence of several crystallographically conserved and buried water molecules. Aided by two novel reaction coordinates involving the distance (d) between the Ca atoms of G60 at switch 2 and G10 at the P-loop and the N-Ca-C-O dihedral (?) of G60, we further show that three water molecules located in lobe1, at the interface between the lobes and at lobe2, are involved in the relative motion of residues at the two lobes of Q61H K-ras. A d/? plot classifies the available Ras x-ray structures and MD-derived K-ras conformers into active GTP-, intermediate GTP-, inactive GDP-bound, and nucleotide-free conformational states. These findings pave the way for a dynamics-guided strategy to inhibit abnormal Ras signaling.

Ras conformational dynamics: Novel-reaction coordinates and role of conserved waters

245th National Meeting (2013)

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