Center for Theoretical Biological Physics, Houston, Texas 77005, United States.
Department of Chemistry, Rice University, Houston, Texas 77005, United States.
J Am Chem Soc. 2022 Feb 2;144(4):1835-1845. doi: 10.1021/jacs.1c11911. Epub 2022 Jan 21.
The accurate reading of genetic information during transcription is essential for the expression of genes. Sequence binding specificity very often is attributed to short-range, usually specific interactions between amino acid residues and individual nucleotide bases through hydrogen bonding or hydrophobic contacts: "base readout" (direct readout). In contrast, many proteins recognize DNA sequences in an alternative fashion via "shape readout" (indirect readout), where many elements of the DNA sequence cooperate to localize the transcription factor. In this study, we use a coarse-grained protein-DNA model to investigate the origin of the sequence specificity of the protein PU.1 binding to its binding sites for a series of DNA sequences. We find that the binding specificity of PU.1 is achieved primarily via a nonspecific electrostatically driven DNA mechanism involving the change in the elastic properties of the DNA. To understand the underlying mechanism, we analyze how the mechanical properties of DNA change in relation to the location of the PU.1 bound along DNA. The simulations first show that electrostatic interactions between PU.1 and DNA can cause complex DNA conformational/dynamics changes. Using a semiflexible polymer theory, we find that PU.1 influences the DNA dynamics through a second-order mechanical effect. When PU.1 binds nonspecifically to the DNA via electrostatics, the DNA becomes stiffer and the protein slides along DNA in a search mode. In contrast, once the protein finds its specific binding site, the DNA becomes softer there. PU.1 thus locks into place through configurational entropy effects, which we suggest is a generic mechanism for indirect readout.
在转录过程中准确读取遗传信息对于基因表达至关重要。序列结合特异性通常归因于氨基酸残基与单个核苷酸碱基之间的短程、通常是特异性相互作用，通过氢键或疏水接触实现：“碱基读取”（直接读取）。相比之下，许多蛋白质通过“形状读取”（间接读取）以替代方式识别 DNA 序列，其中 DNA 序列的许多元素共同定位转录因子。在这项研究中，我们使用粗粒蛋白-DNA 模型来研究蛋白质 PU.1 与其结合位点结合的序列特异性的起源，这些结合位点针对一系列 DNA 序列。我们发现，PU.1 的结合特异性主要通过一种非特异性的静电驱动的 DNA 机制实现，该机制涉及 DNA 弹性特性的变化。为了理解潜在的机制，我们分析了 DNA 的机械性能如何与 PU.1 在 DNA 上的结合位置相关变化。模拟首先表明，PU.1 与 DNA 之间的静电相互作用会导致复杂的 DNA 构象/动力学变化。使用半刚性聚合物理论，我们发现 PU.1 通过二阶机械效应影响 DNA 动力学。当 PU.1 通过静电非特异性地结合 DNA 时，DNA 变得更硬，蛋白质在搜索模式下沿 DNA 滑动。相比之下，一旦蛋白质找到其特定的结合位点，那里的 DNA 就会变软。PU.1 因此通过构象熵效应锁定在适当的位置，我们认为这是间接读取的一种通用机制。
