Ligand Binding Site Identification in Membrane-Bound Oncogenic K-Ras

Abstract

Ras proteins regulate diverse signaling pathways by cycling between active and inactive conformational states. Ras mutations are associated with a variety of cancers and developmental disorders, accounting for ∼15% of all human tumors and 90% of cases in pancreatic cancer. Membrane binding through the hypervariable region is essential for the biological activity of Ras proteins. Understanding isoform-specific differences in membrane binding could therefore lead to new therapeutic strategies. The goal of this work was to find novel druggable sites on the surface of membrane-bound oncogenic K-ras. To this end, we carried out multiple, microsecond-long all-atom molecular dynamics simulations on G12D K-ras and generated a very large structural ensemble. Applying a variety of ligand binding site identification techniques on this ensemble, we identified several pockets that have the potential to bind small molecule ligands. Moreover, we found that some of the previously described ligand-binding sites in solution are inaccessible to ligands in the presence of a membrane. Our analysis also yielded some new insights into the dynamics of membrane-bound oncogenic K-ras.