Computational investigation of proton transfer, pKa shifts and pH-optimum of protein-DNA and protein-RNA complexes.
Computational investigation of proton transfer, pKa shifts and pH-optimum of protein-DNA and protein-RNA complexes.
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蛋白质-核酸相互作用在许多生物过程中发挥着至关重要的作用。这项工作研究了蛋白质-核酸结合时可能发生的可电离基团（包括核酸碱基）的 pKa 值和质子化状态的变化。利用最近开发的pKa计算工具DelphiPka，我们利用大型蛋白质-核酸相互作用数据库（NPIDB数据库）来模拟结合引起的pKa变化。研究发现，蛋白质的界面碱性残基经历有利的静电相互作用，而蛋白质酸性残基经历质子吸收，以降低结合时的能量成本。这与对蛋白质-蛋白质复合物的观察形成对比。就DNA/RNA而言，发现核苷酸的碱基基团和磷酸基团都参与结合。一些 DNA/RNA 碱基在复合物形成时会经历 pKa 变化，结合过程往往会抑制核酸碱基的带电状态。此外，蛋白质-DNA/RNA 结合自由能的最适 pH 值与蛋白质折叠自由能的最适 pH 值之间存在弱相关性。总体而言，预计蛋白质-核酸结合的 pH 依赖性不如蛋白质-蛋白质缔合的 pH 依赖性那么显着。
Protein-nucleic acid interactions play a crucial role in many biological processes. This work investigates the changes of pKa values and protonation states of ionizable groups (including nucleic acid bases) that may occur at protein-nucleic acid binding. Taking advantage of the recently developed pKa calculation tool DelphiPka, we utilize the large protein-nucleic acid interaction database (NPIDB database) to model pKa shifts caused by binding. It has been found that the protein’s interfacial basic residues experience favorable electrostatic interactions while the protein acidic residues undergo proton uptake to reduce the energy cost upon the binding. This is in contrast with observations made for protein-protein complexes. In terms of DNA/RNA, both base groups and phosphate groups of nucleotides are found to participate in binding. Some DNA/RNA bases undergo pKa shifts at complex formation, with the binding process tending to suppress charged states of nucleic acid bases. In addition, a weak correlation is found between the pH-optimum of protein-DNA/RNA binding free energy and the pH-optimum of protein folding free energy. Overall, the pH-dependence of protein-nucleic acid binding is not predicted to be as significant as that of protein-protein association.