Li Zhen, Bhowmik Subhamoy, Sagresti Luca, Brancato Giuseppe, Smith Madelyn, Benson David E, Li Pengfei, Merz Kenneth M
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.
Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy.
J Chem Theory Comput. 2024 Aug 13;20(15):6706-6716. doi: 10.1021/acs.jctc.4c00581. Epub 2024 Jul 31.
One commonly observed binding motif in metalloproteins involves the interaction between a metal ion and histidine's imidazole side chains. Although previous imidazole-M(II) parameters established the flexibility and reliability of the 12-6-4 Lennard-Jones (LJ)-type nonbonded model by simply tuning the ligating atom's polarizability, they have not been applied to multiple-imidazole complexes. To fill this gap, we systematically simulate multiple-imidazole complexes (ranging from one to six) for five metal ions (Co(II), Cu(II), Mn(II), Ni(II), and Zn(II)) which commonly appear in metalloproteins. Using extensive (40 ns per PMF window) sampling to assemble free energy association profiles (using OPC water and standard HID imidazole charge models from AMBER) and comparing the equilibrium distances to DFT calculations, a new set of parameters was developed to focus on energetic and geometric features of multiple-imidazole complexes. The obtained free energy profiles agree with the experimental binding free energy and DFT calculated distances. To validate our model, we show that we can close the thermodynamic cycle for metal-imidazole complexes with up to six imidazole molecules in the first solvation shell. Given the success in closing the thermodynamic cycles, we then used the same extended sampling method for six other metal ions (Ag(I), Ca(II), Cd(II), Cu(I), Fe(II), and Mg(II)) to obtain new parameters. Since these new parameters can reproduce the one-imidazole geometry and energy accurately, we hypothesize that they will reasonably predict the binding free energy of higher-level coordination numbers. Hence, we did not extend the analysis of these ions up to six imidazole complexes. Overall, the results shed light on metal-protein interactions by emphasizing the importance of ligand-ligand interaction and metal-π-stacking within metalloproteins.
金属蛋白中一种常见的结合基序涉及金属离子与组氨酸咪唑侧链之间的相互作用。尽管先前的咪唑 - M(II) 参数通过简单调整配位原子的极化率确定了12 - 6 - 4 Lennard - Jones（LJ）型非键模型的灵活性和可靠性，但它们尚未应用于多咪唑配合物。为了填补这一空白，我们系统地模拟了五种常见于金属蛋白中的金属离子（Co(II)、Cu(II)、Mn(II)、Ni(II) 和 Zn(II)）的多咪唑配合物（从一到六个咪唑）。使用广泛的采样（每个PMF窗口40 ns）来组装自由能缔合曲线（使用OPC水和来自AMBER的标准HID咪唑电荷模型），并将平衡距离与DFT计算结果进行比较，开发了一组新的参数，重点关注多咪唑配合物的能量和几何特征。获得的自由能曲线与实验结合自由能和DFT计算的距离一致。为了验证我们的模型，我们表明我们可以闭合第一溶剂化层中含有多达六个咪唑分子的金属 - 咪唑配合物 的热力学循环。鉴于在闭合热力学循环方面取得的成功，我们随后对其他六种金属离子（Ag(I)、Ca(II)、Cd(II)、Cu(I)、Fe(II) 和 Mg(II)）使用相同的扩展采样方法来获得新参数。由于这些新参数可以准确地再现单咪唑的几何结构和能量，我们假设它们将合理地预测更高配位数的结合自由能。因此，我们没有将这些离子的分析扩展到六个咪唑配合物。总体而言，这些结果通过强调金属蛋白中配体 -配体相互作用和金属 -π堆积的重要性，揭示了金属 - 蛋白相互作用。
