ABSTRACT Sifuvirtide (SFT) is the second generation inhibitor of HIV-1 gp41 fusion protein, which is under phase III clinical trial for anti-HIV. However, over a period of time virus develops resistance against SFT. To overcome resistance, methionine and threonine (MT) amino acids were implemented in the pocket binding domain of SFT namely MT-Sifuvirtide (MTSFT), which have more helicity; higher melting temperature and stability against resistance-virus. To date, the binding stability and functional role of MT-hook against wild type and mutant form of HIV-1 gp41 fusion protein are not known. In the present study, SFT and MTSFT were individually docked with the wild and V10A/A19I/Q24R mutant form of HIV-1 gp41. Further MD simulation was carried out to understand the stability of the ligand–protein complexes. The free energy values were calculated from the MD trajectories to understand the effect of mutation involved in the binding process. MD results revealed helix to loop type conformational changes in N-heptad repeat (NHR) of gp41 due to mutation. Intermolecular interactions reveal that MTSFT forms more strong interactions with NHR of gp41 than SFT, which is critical for six-helix bundle stabilisation. Hence, the results explained the detailed functional role of MT-hook against gp41 fusion at the molecular level.

中文翻译：

---

西夫韦肽和 MT-西夫韦肽对野生和突变 HIV-1 包膜糖蛋白 41 的抑制机制的见解：分子动力学模拟和结合自由能研究

摘要 Sifuvirtide (SFT) 是第二代 HIV-1 gp41 融合蛋白抑制剂，正在进行抗 HIV 的 III 期临床试验。但是，经过一段时间后，病毒会对 SFT 产生抗性。为了克服耐药性，在 SFT 的口袋结合域中实施了甲硫氨酸和苏氨酸 (MT) 氨基酸，即 MT-Sifuvirtide (MTSFT)，它们具有更多的螺旋性；更高的熔解温度和抗病毒稳定性。迄今为止，MT-hook 对野生型和突变型 HIV-1 gp41 融合蛋白的结合稳定性和功能作用尚不清楚。在本研究中，SFT 和 MTSFT 分别与 HIV-1 gp41 的野生和 V10A/A19I/Q24R 突变形式对接。进行了进一步的 MD 模拟以了解配体 - 蛋白质复合物的稳定性。自由能值是从 MD 轨迹计算出来的，以了解结合过程中涉及的突变的影响。MD 结果显示，由于突变，gp41 的 N-七肽重复序列 (NHR) 中的螺旋到环型构象发生变化。分子间相互作用表明，MTSFT 与 gp41 的 NHR 形成比 SFT 更强的相互作用，这对于六螺旋束稳定至关重要。因此，结果在分子水平上解释了 MT-hook 针对 gp41 融合的详细功能作用。这对于六螺旋束稳定至关重要。因此，结果在分子水平上解释了 MT-hook 针对 gp41 融合的详细功能作用。这对于六螺旋束稳定至关重要。因此，结果在分子水平上解释了 MT-hook 针对 gp41 融合的详细功能作用。