Department of Chemical and Biological EngineeringDepartment of Computer Engineering2024-11-0920171520-610610.1021/acs.jpcb.7b030352-s2.0-85021413916http://dx.doi.org/10.1021/acs.jpcb.7b03035https://hdl.handle.net/20.500.14288/10589To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodies-terase-delta (PDE delta) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDE delta/Ras interactions, we modeled and simulated the PDE delta/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDE delta with the farnesylated hypervariable regions K-Ras4A and N-Ras. Earlier data suggested that PDE delta extracts K-Ras4B and N-Ras from the PM, but surprisingly not K-kas4A. Earlier analysis of the crystal structures advanced that the presence of large/charged residues adjacent to the farnesylated site precludes the PDE delta interaction. Here, we show that PDE delta can bind to farnesylated K-Ras4A and N-Ras like K-Ras4B, albeit not as strongly. This weaker binding, coupled with the stronger anchoring of K-Ras4A in the membrane (but not of electrostatically neutral N-Ras), can explain the observation why PDE delta is unable to effectively extract K-Ras4A. We thus propose that farnesylated Ras isoforms can bind PDE delta to fulfill the required PM enrichment, and argue that the different environments, PM versus solution, can resolve apparently puzzling Ras observations. These are novel insights that would not be expected based on the crystal structures alone, which provide an elegant rationale for previously puzzling observations of the differential effects of PDE delta on farnesylated Ras family proteins.ChemistryPhysical chemistryJournal Article1520-52074042020000045655