<br>刺突蛋白突变体与人 β 防御素 2 型结合的分子动力学模拟,The Journal of Physical Chemistry B

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刺突蛋白突变体与人 β 防御素 2 型结合的分子动力学模拟
The Journal of Physical Chemistry B ( IF 2.8 ) Pub Date : 2024-01-08 , DOI: 10.1021/acs.jpcb.3c05460
Liqun Zhang ₁ , Jadeson Li ₂

Affiliation

人β防御素 2 型（hBD-2）是人类先天免疫系统分泌的一种富含半胱氨酸的阳离子肽，可以在与受体 ACE2 相同的位点结合 Spike-RBD，从而阻止病毒进入表达 ACE2 的细胞。为了找出 CoV-2 突变对 hBD-2 抗病毒活性的影响，研究 hBD-2 与 RBD 突变体的结合和相互作用非常重要。对与 hBD-2 结合的典型 RBD 突变体 N501Y、E484K、P479S、T478I、S477N、N439K、K417N 和 N501Y-E484K-K417N 进行全原子分子动力学模拟。从 hBD-2 和 wt-RBD 的稳定结合结构以及 ClusPro 和 HADDOCK 对接预测的初始结构出发，建立与 hBD-2 模拟结合的 RBD 变体，并进行 NAMD 模拟。基于结构和动力学分析，发现大多数 RBD 变体除了具有相似大小的埋藏表面积（BSA）和与 RBD 野生型相似的结合界面外，仍然可以与 hBD-2 形成相似数量的氢键。然而，RBD 三重突变体与 hBD-2 形成的结合结构比其他变体更不稳定。此外，应用自由能扰动（FEP）方法计算关键突变残基对结合的贡献以及突变引起的自由能变化。结果表明，N439K、K417N 和三突变增加了 RBD 与 hBD-2 的结合自由能;因此，RBD 与 hBD-2 的结合稳定性应该较低。E484K 降低了结合自由能，因此它与 hBD-2 的结合应该更稳定，而 N501Y、S477N、T478I 和 P479S 几乎不会改变与 hBD-2 的结合自由能。 MM-GBSA 方法预测了结合相互作用能，这表明三突变体应该能够逃避与 hBD-2 的结合，但 N501Y 不应该。该结果可以为理解 hBD-2 对抗 SARS-CoV-2 突变体的功能机制提供见解。

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Molecular Dynamics Simulations on Spike Protein Mutants Binding with Human β Defensin Type 2

Human β defensin type 2 (hBD-2), a cationic cysteine-rich peptide secreted from the human innate immune system, can bind Spike-RBD at the same site as receptor ACE2, thus blocking viral entry into ACE2-expressing cells. In order to find out the impact of CoV-2 mutations on hBD-2’s antiviral activity, it is important to investigate the binding and interaction of hBD-2 with RBD mutants. All-atom molecular dynamics simulations were conducted on typical RBD mutants, including N501Y, E484K, P479S, T478I, S477N, N439K, K417N, and N501Y-E484K-K417N, binding with hBD-2. Starting from the stable binding structure of hBD-2 and wt-RBD and ClusPro and HADDOCK docking-predicted initial structures, the RBD variants bound with hBD-2 simulations were set up, and NAMD simulations were conducted. Based on the structure and dynamics analysis, it was found that most RBD variants can still form a similar number of hydrogen bonds with hBD-2, in addition to having a similar-sized buried surface area (BSA) and a similar binding interface to the RBD wildtype. However, the RBD triple mutant formed a less stable binding structure with hBD-2 than other variants. Additionally, the free energy perturbation (FEP) method was applied to calculate the contribution of key mutant residues to the binding and the free energy change caused by the mutations. The result shows that N439K, K417N, and the trimutation increase the binding free energy of RBD with hBD-2; thus, RBD should bind less stably with hBD-2. E484K decreases the binding free energy, thus it should bind more stably with hBD-2, while N501Y, S477N, T478I, and P479S almost do not change the binding free energy with hBD-2. The MM-GBSA method predicted the binding interaction energy which shows that the trimutant should be able to escape the binding with hBD-2 but N501Y should not. The result can provide insight into understanding the functional mechanism of hBD-2 combating SARS-CoV-2 mutants.

更新日期：2024-01-08

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