College of Integrative Sciences and Arts , Arizona State University , Mesa , Arizona 85212 , United States.
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases , National Institutes of Health , Bethesda , Maryland 20892-0520 , United States.
J Phys Chem B. 2018 Dec 13;122(49):11478-11487. doi: 10.1021/acs.jpcb.8b07425. Epub 2018 Oct 2.
Protein dynamics often exhibit internal friction; i.e., contributions to friction that cannot solely be attributed to the viscosity of the solvent. Remarkably, even unfolded and intrinsically disordered proteins (IDPs) exhibit this behavior, despite typically being solvent-exposed. Several competing molecular mechanisms have been suggested to underlie this phenomenon, in particular dihedral relaxation and intrachain interactions. It has also recently been shown that single-molecule data reflecting internal friction in the disordered protein ACTR cannot be explained using polymer models unless this friction is dependent on protein collapse. However, the connection between the collapse of the chain and the underlying mechanism of internal friction has been unclear. To address this issue, we combine molecular simulation and single-molecule experimental data to investigate how chain compaction affects protein dynamics in the context of ACTR. Chain reconfiguration times and internal friction estimated from all-atom simulations are in semiquantitative agreement with experimental data. We dissect the underlying molecular mechanism with all-atom and coarse-grained simulations and clearly identify both intrachain interactions and dihedral angle transitions as contributions to internal friction. However, their relative contribution is strongly dependent on the compactness of the IDP; while dihedral relaxation dominates internal friction in expanded configurations, intrachain interactions dominate for more compact chains. Our results thus imply a continuous transition between mechanisms and provide a link between internal friction in IDPs and that in more compact and folded states of proteins.
蛋白质动力学通常表现出内部摩擦；即，摩擦的贡献不能仅仅归因于溶剂的粘度。值得注意的是，即使是展开的和固有无序的蛋白质（IDPs）也表现出这种行为，尽管它们通常是暴露在溶剂中的。已经提出了几种竞争的分子机制来解释这种现象，特别是二面角弛豫和链内相互作用。最近还表明，反映无序蛋白 ACTR 内部摩擦的单分子数据不能用聚合物模型来解释，除非这种摩擦取决于蛋白折叠。然而，链折叠和内部摩擦的潜在机制之间的联系还不清楚。为了解决这个问题，我们结合分子模拟和单分子实验数据来研究链压缩如何影响 ACTR 中蛋白质的动力学。全原子模拟估计的链重排时间和内部摩擦与实验数据具有半定量的一致性。我们用全原子和粗粒化模拟来剖析潜在的分子机制，并清楚地确定链内相互作用和二面角转变都是内部摩擦的贡献。然而，它们的相对贡献强烈依赖于 IDP 的紧凑性；虽然二面角弛豫在展开构象中主导内部摩擦，但对于更紧凑的链，链内相互作用占主导地位。因此，我们的结果意味着机制之间存在连续的转变，并为 IDP 中的内部摩擦与蛋白质更紧凑和折叠状态中的内部摩擦之间建立了联系。
