Presence or absence of Ras-dimerization shows distinct kinetic signature in Ras-Raf interaction

In eukaryotes, MAPK pathways play a central role in making several important cellular decisions, including cell proliferation and development of an organism. Ras, a small GTPase, interacts with the protein Raf to create activated Ras-Raf complex (Raf dimer) that activates the downstream effectors in the ERK pathway, one of the many MAPK pathways. Malfunctioning Ras-Raf “switches” cause almost 30% of all known cancer. Hence, understanding Ras-Raf interaction is of paramount importance. Despite decades of research, the detailed mechanism of Ras-Raf interaction is still unclear. It has been hypothesized that Ras dimerization is necessary to create the activated Raf dimer. Although there are circumstantial evidences supporting the Ras dimerization hypothesis, direct proof of Ras dimerization is still inconclusive. In the absence of conclusive direct experimental proof, this hypothesis can only be examined through indirect evidences of Ras dimerization. In this paper, using a multi-scale simulation technique, we provide multiple criteria that distinguishes an activation mechanism involving Ras dimerization from another mechanism that does not involve Ras dimerization. The provided criteria will be useful in the investigation of not only Ras-Raf interaction but also other two-protein interactions.