3MBA类FtsZ蛋白抑制剂的分子动力学模拟及抗菌作用机制

采用分子动力学模拟、蛋白质二级结构测定(DSSP)、口袋体积测量(POVME)以及MM-PBSA(molecular mechanics Poisson-Boltzmann surface area)方法, 系统研究了金黄色葡萄球菌丝状温度敏感性蛋白Z (SaFtsZ)-二磷酸鸟苷(GDP)二元复合物和SaFtsZ-GDP-3MBA (3-甲氧基苯甲酰胺)类衍生物三元复合物体系的稳定性、蛋白质二级结构、蛋白质构象、关键残基质心距、活性口袋体积以及相对结合自由能的变化规律. 研究表明: 当不含抑制剂存在时SaFtsZ-GDP二元复合物体系稳定性较差, 其T7Loop区域残基(203-209)波动较大, 且蛋白二级结构发生明显变化, 活性口袋体积急剧减小, 底物通道显著变窄且不稳定. 而含有抑制剂PC190723、Compound1 的类衍生物三元复合物体系的表现截然不同, 这主要是由于它们均能和活性口袋T7Loop区周围残基形成关键性的氢键以及疏水作用, 与FtsZ 蛋白紧密结合. 在SaFtsZ-GDP-3MBA三元复合物体系中, 3MBA仅能与活性口袋中部分残基形成疏水作用, 与FtsZ 蛋白亲和力较弱, 使其不能稳定地存在于活性口袋中, 进一步导致它的抗菌活性明显低于PC190723、Compound1. 这些发现深入揭示了3MBA类衍生物对FtsZ 蛋白的作用机制和影响规律, 为该类FtsZ 蛋白抑制剂的结构优化和产品开发应用提供了重要的理论依据.

Molecular Dynamics Simulation and Antibacterial Mechanism of 3MBA Derivatives as FtsZ Protein Inhibitors

In this paper, the complex stability, secondary structure, protein conformation, residue distance, active site volume, and binding free energy of the binary complex of filamentous sensitivity division protein Z of Staphylococcus aureus-guanosine diphosphate (SaFtsZ-GDP) and the ternary complex of SaFtsZ-GDP- 3MBA (3-methoxybenzamide) derivatives were studied using molecular dynamics simulations, definition of secondary structure of proteins (DSSP), pocket volume measurer (POVME), and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. The results show that the SaFtsZ-GDP binary complex was unstable in the absence of inhibitor, and the residues of its T7Loop area (residues 203-209) show obvious fluctuations. The secondary structure of the protein in the T7Loop area also changes significantly, the active pocket volume decreases dramatically and the substrate channel size becomes narrow and unstable. However, the SaFtsZ-GDP-3MBA derivatives ternary complex looks completely different in the presence of inhibitor PC190723 or Compound 1. Both of the inhibitors can form hydrogen bonds and hydrophobic interactions with high affinity to FtsZ. However, the ligand only forms hydrophobic interactions with partial residues of the active site as a function of simulation time in the SaFtsZ-GDP-3MBA ternary complex. This low affinity means that 3MBA cannot stably exist in the active site, and so the antibacterial activity of 3MBA is significantly lower than that of PC190723 or Compound 1. The study shows the antibacterial mechanism and effect of 3MBA derivatives on FtsZ, and provides an important theoretical basis for inhibitor structural optimization, development and applications.