Long-lasting Salt Bridges Provide the Anchoring Mechanism of Oncogenic Kirsten Rat Sarcoma Proteins at Cell Membranes.

RAS proteins work as GDP-GTP binary switches and regulate cytoplasmic signaling networks that are able to control several cellular processes, playing an essential role in signal transduction pathways involved in cell growth, differentiation, and survival, so that overacting RAS signaling can lead to cancer. One of the hardest challenges to face is the design of mutation-selective therapeutic strategies. In this work, a G12D-mutated farnesylated GTP-bound Kirsten RAt sarcoma (KRAS) protein has been simulated at the interface of a DOPC/DOPS/cholesterol model anionic cell membrane. A specific long-lasting salt bridge connection between farnesyl and the hypervariable region of the protein has been identified as the main mechanism responsible for the binding of oncogenic farnesylated KRAS-4B to the cell membrane. Free-energy landscapes allowed us to characterize local and global minima of KRAS-4B binding to the cell membrane, revealing the main pathways between anchored and released states.