Department of Physics, Technical University of Catalonia-Barcelona Tech, B4-B5 Northern Campus, Barcelona, Catalonia, Spain.
J Phys Chem Lett. 2020 Nov 19;11(22):9938-9945. doi: 10.1021/acs.jpclett.0c02809. Epub 2020 Nov 10.
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.
RAS 蛋白作为 GDP-GTP 二联体开关，调节细胞质信号网络，能够控制多种细胞过程，在涉及细胞生长、分化和存活的信号转导途径中发挥重要作用，因此过度活跃的 RAS 信号可能导致癌症。面临的最艰巨挑战之一是设计突变选择性治疗策略。在这项工作中，模拟了 G12D 突变的法尼基化 GTP 结合 Kirsten RAt 肉瘤（KRAS）蛋白与 DOPC/DOPS/胆固醇模型阴离子细胞膜的界面。已经确定法尼基和蛋白质的高变区之间的特定持久盐桥连接是致癌法尼基化 KRAS-4B 与细胞膜结合的主要机制。自由能景观使我们能够表征 KRAS-4B 与细胞膜结合的局部和全局最小值，揭示了锚定状态和释放状态之间的主要途径。
