K-Ras is one of the most frequently mutated oncogenes in human tumor cells. It consists of a well-conserved globular catalytic domain and a flexible tail-like hypervariable region (HVR) at its C-terminal end. It plays a key role in signaling networks in proliferation, differentiation, and survival, undergoing a conformational switch between the active and inactive states. It is regulated through the GDP-GTP cycle of the inactive GDP-bound and active GTP-bound states. Here, without imposing any prior constraints, we mapped the interaction pattern between the catalytic domain and the HVR using Molecular Dynamics with excited Normal Modes (MDeNM) starting from an initially extended HVR conformation for both states. Our sampling captured similar interaction patterns in both GDP- and GTP-bound states with shifted populations depending on the bound nucleotide. In the GDP-bound state, the conformations where the HVR interacts with the effector lobe are more populated than in the GTP-bound state, forming a buried thus autoinhibited catalytic site; in the GTP-bound state conformations where the HVR interacts with the allosteric lobe are more populated, overlapping the α3/α4 dimerization interface. The interaction of the GTP with Switch I and Switch II is stronger than that of the GDP in line with a decrease in the fluctuation upon GTP binding.

K-Ras是人类肿瘤细胞中最常见的致癌基因之一。它由一个保守的球状催化结构域和一个位于其C末端的柔性尾状高变区（HVR）组成。它在增殖，分化和存活的信号网络中起关键作用，在活跃状态和非活跃状态之间进行构象转换。它由处于非活动状态的受GDP约束和处于活动状态的受GTP约束的国家的GDP-GTP周期进行调节。在这里，在不施加任何先验约束的情况下，我们使用分子动力学和激发态模式（MDeNM）从两个状态的初始扩展HVR构象出发，绘制了催化域与HVR之间的相互作用模式。我们的采样在与GDP和GTP结合的状态下捕获了相似的相互作用模式，并且种群的迁移取决于结合的核苷酸。在与GDP结合的状态下，与在与GTP结合的状态下相比，HVR与效应子相互作用的构象更为密集，从而形成了一个被掩埋的自动抑制的催化位点。在HTP与变构叶相互作用的GTP结合状态构象中，与α3/α4二聚化界面重叠的人较多。GTP与Switch I和Switch II的相互作用要强于GDP，这与GTP绑定时波动的减少相一致。在HTP与变构叶相互作用的GTP结合状态构象中，与α3/α4二聚化界面重叠的人较多。GTP与Switch I和Switch II的相互作用要强于GDP，这与GTP绑定时波动的减少相一致。在HTP与变构叶相互作用的GTP结合状态构象中，与α3/α4二聚化界面重叠的人较多。GTP与Switch I和Switch II的相互作用要强于GDP，这与GTP绑定时波动的减少相一致。