Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.
Institute of Medical Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary; MTA-SZTE Biomimetic Systems Research Group, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
J Inorg Biochem. 2021 Mar;216:111330. doi: 10.1016/j.jinorgbio.2020.111330. Epub 2020 Dec 8.
Our goal was to explore the possible interactions of the potential metallodrug (η-Cp*)Rh(III) complexes with histidine containing biomolecules (peptides/proteins) in order to understand the most important thermodynamic factors influencing the biospeciation and biotransformation of (η-Cp*)Rh(III) complexes. To this end, here we report systematic solution thermodynamic and solution structural study on the interaction of (η-Cp*)Rh(III) cation with histidine containing peptides and their constituents ((N-methyl)imidazole, GGA-OH, GGH-OH, histidine-amide, HGG-OH, GHG-NH), based on extensive H NMR, ESI-MS and potentiometric investigations. The comparative evaluation of our data indicated that (η-Cp*)Rh(III) cation is able to induce the deprotonation of amide nitrogen well below pH 7. Consequently, at physiological pH the peptides are coordinated to Rh(III) by tridentate manner, with the participation of amide nitrogen. At pH 7.4 the (η-Cp*)Rh(III) binding affinity of peptides follow the order GGA-OH < < GGH-OH < < histidine-amide < HGG-OH < GHG-NH, i.e. the observed binding strength essentially depends on the presence and position of histidine within the peptide sequence. We also performed computational study on the possible solution structures of complexes present at near physiological pH. At pH 7.4 all histidine containing peptides form ternary complexes with strongly coordinating (N,N) bidentate ligands (ethylenediamine or bipyridyl), in which the peptides are monodentately coordinated to Rh(III) through their imidazole N‑nitrogens. In addition, the strongest chelators histidine-amide, HGG-OH and GHG-NH are also able to displace these powerful bidentate ligands from the coordination sphere of Rh(III).
我们的目标是探索潜在的金属药物（η-Cp*）Rh（III）配合物与含组氨酸的生物分子（肽/蛋白质）之间可能的相互作用，以便了解影响（η-Cp*）Rh（III）配合物生物形态和生物转化的最重要热力学因素。为此，我们在这里报告了对（η-Cp*）Rh（III）阳离子与含组氨酸的肽及其组成部分（（N-甲基）咪唑，GGA-OH，GGH-OH，组氨酸酰胺，HGG-OH，GHG-NH）相互作用的系统溶液热力学和溶液结构研究，这是基于广泛的 H NMR，ESI-MS 和电位研究。我们的数据比较评估表明，（η-Cp*）Rh（III）阳离子能够诱导酰胺氮的去质子化，其程度远低于 pH 7。因此，在生理 pH 下，肽通过三齿配位方式与 Rh（III）配位，酰胺氮参与配位。在 pH 7.4 下，肽与（η-Cp*）Rh（III）的结合亲和力顺序为 GGA-OH << GGH-OH << 组氨酸酰胺 < HGG-OH < GHG-NH，即观察到的结合强度主要取决于肽序列中组氨酸的存在和位置。我们还对近生理 pH 下存在的配合物的可能溶液结构进行了计算研究。在 pH 7.4 下，所有含组氨酸的肽都与强配位的（N，N）双齿配体（乙二胺或联吡啶）形成三元配合物，其中肽通过其咪唑 N-氮原子以单齿方式与 Rh（III）配位。此外，最强的螯合剂组氨酸酰胺，HGG-OH 和 GHG-NH 也能够从 Rh（III）的配位球中置换这些强双齿配体。
