Unraveling the Allosteric Inhibition Mechanism of PTP1B by Free Energy Calculation Based on Umbrella Sampling
Unraveling the Allosteric Inhibition Mechanism of PTP1B by Free Energy Calculation Based on Umbrella Sampling
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基于伞采样的自由能计算揭示PTP1B变构抑制机制
DOI：
10.1021/ci300526u
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发表时间：
2013-05-01
影响因子：
5.6
通讯作者：
Ji, Ming-Juan
中科院分区：
文献类型：
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作者：
Cui, Wei;Cheng, Yuan-Hua;Ji, Ming-Juan
蛋白酪氨酸磷酸酶 1B (PTP1B) 是治疗肥胖和 II 型糖尿病的一个有前景的靶点。变构抑制剂可以通过阻碍 PTP1B WPD 环从开放状态到闭合状态的构象转变来稳定 PTP1B 的活性构象。这里，采用伞形采样分子动力学（MD）模拟来计算PTP1B构象转变的反应路径，并根据关键构象参数将从MD轨迹中提取的快照聚类成58个构象组。然后，通过MM/GBSA结合自由能计算和自由能分解分析，探讨了WPD环的构象变化对PTP1B变构位点与变构抑制剂BB3之间相互作用的影响。模拟结果表明，BB3的结合自由能从WPD环的开放构象到闭合构象逐渐增加，提供了变构抑制的分子机制。不同能量项的相关分析表明，负范德华贡献越大的变构抑制剂不仅表现出更强的结合亲和力，而且能更有效地阻碍WPD环的摆动。此外，我们发现α7螺旋中Lys292的能量贡献发生了显着变化，这表明Lys292不仅是配体结合的关键残基，而且在阻碍WPD环的构象变化中发挥着重要作用。
Protein tyrosine phosphatase 1B (PTP1B) is a promising target for the treatment of obesity and type II diabetes. Allosteric inhibitors can stabilize an active conformation of PTP1B by hindering the conformational transition of the WPD loop of PTP1B from the open to the closed state. Here, the umbrella sampling molecular dynamics (MD) simulations were employed to compute the reaction path of the conformational transition of PTP1B, and the snapshots extracted from the MD trajectory were clustered into 58 conformational groups based on the key conformational parameter. Then, the impact of the conformational change of the WPD loop on the interactions between the allosteric site of PTP1B and an allosteric inhibitor BB3 was explored by using the MM/GBSA binding free energy calculations and free energy decomposition analysis. The simulation results show that the binding free energy of BB3 increases gradually from the open to the closed conformation of the WPD loop, providing the molecular mechanism of allosteric inhibition. Correlation analysis of the different energy terms indicates that the allosteric inhibitor with more negative van der Waals contribution cannot only exhibit stronger binding affinity but also hinder the swing of the WPD loop more effectively. Besides, it is found that the energy contribution of Lys292 in the α7 helix undergoes significant change, which reveals that Lys292 is not only the key residue for ligand binding but also plays an important role in hindering the conformational change of the WPD loop.