Prediction of the binding modes between macrolactin N and peptide deformylase from Staphylococcus aureus by molecular docking and molecular dynamics simulations
Prediction of the binding modes between macrolactin N and peptide deformylase from Staphylococcus aureus by molecular docking and molecular dynamics simulations
复制标题
通过分子对接和分子动力学模拟预测大环内酯N与金黄色葡萄球菌肽去酰基酶之间的结合模式
DOI：
10.1007/s00044-012-0303-8
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发表时间：
2013-06-01
影响因子：
2.6
通讯作者：
Ji, Mingjuan
中科院分区：
文献类型：
--
作者：
Gao, Jian;Cheng, Yuanhua;Ji, Mingjuan
Macrolactin N是一种新的内酯化合物，对金黄色葡萄球菌肽脱甲酰基酶（PDF）的IC 50值为7.5 μ M，而其与PDF的结合模式仍然在很大程度上未知。在这项研究中，结合机制macrolactin N PDF的分子对接，分子动力学（MD）模拟和自由能计算进行了研究。通过FlexX对接和聚类分析得到4种典型的结合模式，分别命名为Model A、Model B、Model C和Model D。模型A预测的结合自由能比其他三个模型更稳定。此外，自由能分解和结构分析，以及氢键占有率分析进一步表明，模型A是最适合的配体结合的构象。我们发现模型A中的Zn 2+离子对配体有正贡献，这意味着在该模型上引入金属螯合官能团可以进一步提高与PDF的结合亲和力。我们的分子对接和分子动力学模拟工作的结果的可行性进行了检查的结果PDF-放线菌素在理论模拟和实验结果（例如，晶体结构）。同时，通过与放线菌素结合模式的比较，验证了4种预测的结合模式，比较结果表明，模型A中的大环内酯N与放线菌素结合模式的相似性最高。这项工作可能有助于设计更有前途的PDF抑制剂。
Macrolactin N is a novel lactone compound against Staphylococcus aureus peptide deformylase (PDF) with an IC50 value of 7.5 mu M, while its binding mode with PDF still remains largely unknown. In this study, the binding mechanism of macrolactin N to PDF was investigated using molecular docking, molecular dynamics (MD) simulations, and free energy calculations. Four typical binding modes were obtained by FlexX docking and cluster analysis, which are named as Model A, Model B, Model C, and Model D. The predicted binding free energy of Model A is more stable than those of the other three models. Besides, the free energy decomposition and structure analysis, as well as the hydrogen bond occupancy analysis further demonstrate that Model A is the most appropriate conformation for ligand binding. We found that the Zn2+ ion in Model A has positive contribution with the ligand, which implies the introduction of a metal chelating functional group on this model could further improve the binding affinity to PDF. The feasibility of the results of our molecular docking and MD simulation work was examined by the result about PDF-actinonin in terms of the theoretical simulation and the experimental results (e.g., crystal structure). Meanwhile, four predicted binding modes are validated by means of comparing their binding modes with actinonin, and the comparison result shows that the macrolactin N in Model A may have the highest similarity to the binding mode of actinonin. This work might be useful in designing more promising PDF inhibitors.