Ras is a lipid-modified GTPase that acts as a molecular switch by cycling between active and inactive conformational states. Somatic mutations in Ras are associated with a variety of cancers and are found in ~15% of human tumors. Of the three major human Ras isoforms H-, N- and K-ras, cancers associated with mutant K-ras are the most lethal. Characterization and targeting of hot-spot residues required for the dynamic assembly of Ras on the plasma membrane could be of therapeutic relevance and may yield isoform-specific drugs. To this end, we carried out extensive protein-protein docking combined with all-atom molecular dynamics (MD) simulations to determine the homo-dimeric interface formed by an oncogenic G12D K-ras mutant. Different docking approaches resulted in the identification of similar dimer models. In silico mutagenesis and MD-optimization of these models in membrane revealed hot-spot residues that likely form the dimer interface. Multiple long simulations of membrane-bound monomeric G12D K-ras with and without molecular probes further support the accessibility and suitability of the hot-spot residues for dimer formation.

Abrogating Ras abnormal function by targeting Ras oligomers: Identification of dimer interface for oncogenic K-Ras

248th National Meeting (2014)

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