Rocha-Santos Acassio, Chaves Elton José Ferreira, Grillo Igor Barden, de Freitas Amanara Souza, Araújo Demétrius Antônio Machado, Rocha Gerd Bruno
Department of Chemistry, Federal University of Paraíba, Cidade Universitária, João Pessoa, PB 58051-900, Brazil.
Department of Biotechnology, Federal University of Paraíba, Cidade Universitária, João Pessoa, PB 58051-900, Brazil.
ACS Omega. 2021 Mar 23;6(13):8764-8777. doi: 10.1021/acsomega.0c02588. eCollection 2021 Apr 6.
In this work, we performed a study to assess the interactions between the ricin toxin A (RTA) subunit of ricin and some of its inhibitors using modern semiempirical quantum chemistry and ONIOM quantum mechanics/molecular mechanics (QM/MM) methods. Two approaches were followed (calculation of binding enthalpies, Δ , and reactivity quantum chemical descriptors) and compared with the respective half-maximal inhibitory concentration (IC) experimental data, to gain insight into RTA inhibitors and verify which quantum chemical method would better describe RTA-ligand interactions. The geometries for all RTA-ligand complexes were obtained after running classical molecular dynamics simulations in aqueous media. We found that single-point energy calculations of Δ with the PM6-DH+, PM6-D3H4, and PM7 semiempirical methods and ONIOM QM/MM presented a good correlation with the IC data. We also observed, however, that the correlation decreased significantly when we calculated Δ after full-atom geometry optimization with all semiempirical methods. Based on the results from reactivity descriptors calculations for the cases studied, we noted that both types of interactions, molecular overlap and electrostatic interactions, play significant roles in the overall affinity of these ligands for the RTA binding pocket.
在这项工作中，我们进行了一项研究，采用现代半经验量子化学方法和ONIOM量子力学/分子力学（QM/MM）方法来评估蓖麻毒素的蓖麻毒素A（RTA）亚基与其一些抑制剂之间的相互作用。我们采用了两种方法（结合焓Δ的计算以及反应性量子化学描述符），并与各自的半数最大抑制浓度（IC）实验数据进行比较，以深入了解RTA抑制剂，并验证哪种量子化学方法能更好地描述RTA-配体相互作用。在水性介质中进行经典分子动力学模拟后，获得了所有RTA-配体复合物的几何结构。我们发现，使用PM6-DH +、PM6-D3H4和PM7半经验方法以及ONIOM QM/MM进行的Δ单点能量计算与IC数据呈现出良好的相关性。然而，我们还观察到，当使用所有半经验方法在全原子几何优化后计算Δ时，相关性显著降低。基于所研究案例的反应性描述符计算结果，我们注意到分子重叠和静电相互作用这两种相互作用类型在这些配体对RTA结合口袋的整体亲和力中都起着重要作用。
