Bigman Lavi S, Greenblatt Harry M, Levy Yaakov
Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
J Phys Chem B. 2021 Apr 1;125(12):3119-3131. doi: 10.1021/acs.jpcb.1c00757. Epub 2021 Mar 23.
DNA-binding proteins rely on linear diffusion along the longitudinal DNA axis, supported by their nonspecific electrostatic affinity for DNA, to search for their target recognition sites. One may therefore expect that the ability to engage in linear diffusion along DNA is universal to all DNA-binding proteins, with the detailed biophysical characteristics of that diffusion differing between proteins depending on their structures and functions. One key question is whether the linear diffusion mechanism is defined by translation coupled with rotation, a mechanism that is often termed sliding. We conduct coarse-grained and atomistic molecular dynamics simulations to investigate the minimal requirements for protein sliding along DNA. We show that coupling, while widespread, is not universal. DNA-binding proteins that slide along DNA transition to uncoupled translation-rotation (i.e., hopping) at higher salt concentrations. Furthermore, and consistently with experimental reports, we find that the sliding mechanism is the less dominant mechanism for some DNA-binding proteins, even at low salt concentrations. In particular, the toroidal PCNA protein is shown to follow the hopping rather than the sliding mechanism.
DNA结合蛋白依靠沿DNA长轴的线性扩散来寻找其靶标识别位点，这种扩散由它们对DNA的非特异性静电亲和力所支持。因此，人们可能会认为，沿DNA进行线性扩散的能力是所有DNA结合蛋白所共有的，只是不同蛋白质的这种扩散的详细生物物理特性因其结构和功能而异。一个关键问题是，线性扩散机制是否由平移与旋转耦合所定义，这种机制通常被称为滑动。我们进行了粗粒度和原子尺度的分子动力学模拟，以研究蛋白质沿DNA滑动的最低要求。我们发现，虽然耦合现象普遍存在，但并非所有情况都是如此。沿DNA滑动的DNA结合蛋白在较高盐浓度下会转变为非耦合的平移-旋转（即跳跃）。此外，与实验报告一致，我们发现对于某些DNA结合蛋白而言，即使在低盐浓度下，滑动机制也不是主要机制。特别是，环形增殖细胞核抗原（PCNA）蛋白被证明遵循跳跃而非滑动机制。
