Abstract：
Molecular dynamics simulations were applied to human 5-LOX to obtain detailed information on its structure and dynamics with and without ligands. The dynamical properties evaluated based on root mean square deviations, root mean square fluctuations and secondary structure prediction helped decipher the contrast dynamic behavior of the systems pointing toward the ligand binding effect. The ligand binding to the protein also perturbed other properties of the protein such as the central bending of the protein and water coordination to the metal ion. The central bending in the protein was reported to be very significant that was associated with the allosteric modulation in the lipoxygenases; therefore, on a similar line, the central bending was evaluated in terms of hinge angle analysis which showed substantial bending between the C-terminal and the N-terminal domain via the linker residues which connects the two domains. On the other hand, the suspected water coordination to the metal ion in the protein was ruled out by computing the iron-water radial distribution function which showed that the water molecule was not found to be in the vicinity of the metal ion. Finally, the binding free energy was estimated for Zileuton and CAPE1 inhibitors bound to 5-LOX via the thermodynamic integration approach which showed that CAPE1 had a strong binding potential for the active site of the protein compared to Zileuton, and the free energy data correlated well with their IC50 values corresponding to the high inhibition potential of CAPE1 compared to Zileuton.
摘要：
将分子动力学模拟应用于人类5-LOX，以获得有关在有和没有配体的情况下其结构和动力学的详细信息。基于均方根偏差评估的动力学特性，均方根波动和二级结构预测有助于破译指向配体结合效应的系统的对比动态行为。与蛋白质结合的配体还扰乱蛋白质的其他性质,例如蛋白质的中心弯曲和与金属离子配位的水。据报道，蛋白质的中心弯曲非常重要，与脂氧合酶的变构调节有关；因此，在类似的一条线上，根据铰链角度分析评估中心弯曲,其显示经由连接两个结构域的接头残基在C末端和N末端结构域之间的显著弯曲。另一方面,通过计算铁水径向分布函数排除了蛋白质中与金属离子的可疑水配位，该函数表明未发现水分子在金属离子附近。最后,通过热力学积分方法估计了与5-LOX结合的Zileuton和CAPE1抑制剂的结合自由能，这表明与Zileuton相比，CAPE1对蛋白质的活性位点具有很强的结合潜力，并且自由能数据与它们的IC50值密切相关，对应于CAPE1与Zileuton相比的高抑制电位。
