Heinrich Frank, Van Que N, Jean-Francois Frantz, Stephen Andrew G, Lösche Mathias
Department of Physics, Carnegie Mellon University, Pittsburgh, Pennsylvania; Center for Neutron Research, National Institute of Standards and Technology, Gaithersburg, Maryland.
National Cancer Institute RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.
Biophys J. 2021 Sep 21;120(18):4055-4066. doi: 10.1016/j.bpj.2021.08.008. Epub 2021 Aug 10.
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。此前塑造我们对KRAS信号传导机制理解的分子动力学模拟预测，与最近来自中子反射测量、核磁共振和热力学结合研究的实验结果不一致。为了深入了解这些差异，我们将这一系列生物物理数据与来自一系列实施不同分子相互作用子集的分子模拟的反算实验结果进行比较。我们的结果表明，KRAS4B在含有30%磷脂酰丝氨酸脂质的模型膜上近似于一种熵构型集合，这并没有受到KRAS4B球状G结构域与脂质膜之间相互作用的显著影响。这些发现修正了我们对KRAS信号传导的理解，并推动了一种模型，即蛋白质以近乎均匀的方式采样可及的构象空间，同时能够与效应蛋白结合。
