Previous studies have shown the porphobilinogen synthase (PBGS) zinc-binding mechanism and its conservation among the living cells. However, the precise molecular interaction of zinc with the active center of the enzyme is unknown. In particular, quantum chemistry techniques within the density functional theory (DFT) framework have been the key methodology to describe metalloproteins, when one is looking for a compromise between accuracy and computational feasibility. Considering this, we used DFT-based models within the molecular fractionation with conjugate caps scheme to evaluate the binding energy features of zinc interacting with the human PBGS. Besides, phylogenetic and clustering analyses were successfully employed in extracting useful information from protein sequences to identify groups of conserved residues that build the ions-binding site. Our results also report a conservative assessment of the relevant amino acids, as well as the benchmark analysis of the calculation models used. The most relevant intermolecular interactions in Zn2+-PBGS are due to the amino acids CYS0122, CYS0124, CYS0132, ASP0169, SER0168, ARG0221, HIS0131, ASP0120, GLY0133, VAL0121, ARG0209, and ARG0174. Among these residues, we highlighted ASP0120, GLY0133, HIS0131, SER0168, and ARG0209 by co-occurring in all clusters generated by unsupervised clustering analysis. On the other hand, the triple cysteines at 2.5 Å from zinc (CYS0122, CYS0124, and CYS0132) have the highest energy attraction and are absent in the taxa Viridiplantae, Sar, Rhodophyta, and some Bacteria. Additionally, the performance of the DFT-based models shows that the processing time-dependence is more associated with the choice of the basis set than the exchange-correlation functional.

中文翻译：

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通过量子生物化学和进化方法探索人胆色素原合酶金属蛋白。

先前的研究表明胆色素原合酶 (PBGS) 锌结合机制及其在活细胞中的保守性。然而，锌与酶活性中心的精确分子相互作用是未知的。特别是，当人们正在寻找准确性和计算可行性之间的折衷时，密度泛函理论 (DFT) 框架内的量子化学技术一直是描述金属蛋白的关键方法。考虑到这一点，我们在具有共轭帽方案的分子分级中使用基于 DFT 的模型来评估锌与人类 PBGS 相互作用的结合能特征。除了，系统发育和聚类分析成功地用于从蛋白质序列中提取有用的信息，以识别构建离子结合位点的保守残基组。我们的结果还报告了对相关氨基酸的保守评估，以及所用计算模型的基准分析。Zn2+-PBGS 中最相关的分子间相互作用是由于氨基酸 CYS0122、CYS0124、CYS0132、ASP0169、SER0168、ARG0221、HIS0131、ASP0120、GLY0133、VAL0121、ARG4 在这些残基中，我们突出显示了 ASP0120、GLY0133、HIS0131、SER0168 和 ARG0209，它们共同出现在由无监督聚类分析生成的所有簇中。另一方面，距离锌 2.5 Å 处的三重半胱氨酸（CYS0122、CYS0124、和 CYS0132) 具有最高的能量吸引力，并且在 Viridiplantae、Sar、Rhodophyta 和一些细菌中不存在。此外，基于 DFT 的模型的性能表明，与交换相关函数相比，处理时间依赖性与基组的选择更相关。