Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai 600036, India.
Phys Chem Chem Phys. 2020 Jun 10;22(22):12671-12677. doi: 10.1039/d0cp01758b.
The nature and distribution of charged residues on the surface of proteins play a vital role in determining the binding affinity, selectivity and kinetics of association to ligands. When it comes to DNA-binding domains (DBDs), these functional features manifest as anisotropic distribution of positively charged residues on the protein surface driven by the requirement to bind DNA, a highly negatively charged polymer. In this work, we compare the thermodynamic behavior of nine different proteins belonging to three families - LacR, engrailed and Brk - some of which are disordered in solution in the absence of DNA. Combining detailed electrostatic calculations and statistical mechanical modeling of folding landscapes at different distances and relative orientations with respect to DNA, we show that non-specific electrostatic interactions between the protein and DNA can promote structural transitions in DBDs. Such quinary interactions that are strictly agnostic to the DNA sequence induce varied behaviors including folding of disordered domains, partial unfolding of ordered proteins and (de-)population of intermediate states. Our work highlights that the folding landscape of proteins can be tuned as a function of distance from DNA and hints at possible reasons for DBDs exhibiting complex kinetic-thermodynamic behaviors in the absence of DNA.
蛋白质表面带电残基的性质和分布在决定与配体结合的亲和力、选择性和动力学方面起着至关重要的作用。当涉及到 DNA 结合域 (DBD) 时，这些功能特征表现为蛋白质表面上带正电荷的残基的各向异性分布，这是由与高度带负电荷的聚合物 DNA 结合的要求驱动的。在这项工作中，我们比较了属于三个家族的九种不同蛋白质的热力学行为 - LacR、engrailed 和 Brk - 其中一些在没有 DNA 的情况下在溶液中处于无序状态。通过结合详细的静电计算和对不同距离和相对取向的折叠景观的统计力学建模，我们表明蛋白质和 DNA 之间的非特异性静电相互作用可以促进 DBD 的结构转变。这种与 DNA 序列严格无关的五重相互作用诱导了不同的行为，包括无序结构域的折叠、有序蛋白质的部分展开和中间态的（去）占据。我们的工作强调了蛋白质的折叠景观可以作为与 DNA 距离的函数进行调整，并暗示了 DBD 在没有 DNA 的情况下表现出复杂的动力学-热力学行为的可能原因。
