KRAS4B is a membrane-anchored signaling protein and a primary target in cancer research. Predictions from molecular dynamics simulations that have previously shaped our mechanistic understanding of KRAS signaling disagree with recent experimental results from neutron reflectometry, NMR, and thermodynamic binding studies. To gain insight into these discrepancies, we compare this body of biophysical data to back-calculated experimental results from a series of molecular simulations that implement different subsets of molecular interactions. Our results show that KRAS4B approximates an entropic ensemble of configurations at model membranes containing 30% phosphatidylserine lipids, which is not significantly shaped by interactions between the globular G-domain of KRAS4B and the lipid membrane. These findings revise our understanding of KRAS signaling and promote a model in which the protein samples the accessible conformational space in a near-uniform manner while being available to bind to effector proteins.

KRAS4B 是一种膜锚定信号蛋白，也是癌症研究的主要靶点。分子动力学模拟的预测先前塑造了我们对 KRAS 信号传导机制的理解，但与中子反射计、核磁共振和热力学结合研究的最新实验结果不一致。为了深入了解这些差异，我们将生物物理数据与一系列分子模拟的反算实验结果进行比较，这些分子模拟实现了分子相互作用的不同子集。我们的结果表明，KRAS4B 近似于含有 30% 磷脂酰丝氨酸脂质的模型膜上的构型的熵整体，KRAS4B 的球状 G 结构域与脂质膜之间的相互作用并未显着影响其形状。这些发现修正了我们对 KRAS 信号传导的理解，并推广了一种模型，在该模型中，蛋白质以近乎均匀的方式对可接近的构象空间进行采样，同时可与效应蛋白结合。