Molecular mechanism of the association and dissociation of Deltarasin from the heterodimeric KRas4B-PDEδ complex

The formation of the KRas4B-PDEδ complex activates different signaling pathways required for the development and maintenance of cancer. Previous experimental and theoretical studies have allowed researchers to design an inhibitor of the KRas4B-PDEδ complex, "Deltarasin." This inhibitor binds to the prenyl-binding pocket of PDEδ and subsequently inhibits the proliferation of human pancreatic ductal adenocarcinoma cells that depend on oncogenic KRas4B. Nevertheless, structural and energetic information about the inhibitory effects of Deltarasin on the KRas4B-PDEδ complex are not available. In this study, we explore the properties of Deltarasin in inhibiting the formation of wild-type and mutant KRas4B-PDEδ complexes present in different cell lines expressing mutant RAS genes (G12D, G12C, G12V, G13D, Q61L, and Q61R) using 1.7 μs molecular dynamics (MD) simulations in combination with the MMGBSA approach. Our results revealed the energetic and structural mechanisms that suggest a higher affinity of Deltarasin for PDEδ than the farnesylated HVR. Moreover, Deltarasin exerts another dissociative effect by binding to the protein-protein dimeric interface of wild-type KRas4B-PDEδ, whereas associative and dissociative effects were observed for mutant KRas4B-PDEδ, providing a mechanistic explanation for the inhibitory effects of Deltarasin on different cancer cell lines.