The HIV-1 capsid is an irregularly shaped protein complex containing the viral genome and several proteins needed for integration into the host cell genome. Small molecules, such as the drug-like compound PF-3450074 (PF74) and the anionic sugar inositolhexakisphosphate (IP6), are known to impact capsid stability, although the mechanisms through which they do so remain unknown. In this study, we employed atomistic molecular dynamics simulations to study the impact of molecules bound to hexamers at the central pore (IP6) and the FG-binding site (PF74) on the interface between capsid oligomers. We found that the IP6 cofactor stabilizes a pair of neighboring hexamers in their flattest configurations, whereas PF74 introduces a strong preference for intermediate tilt angles. These results suggest that the tilt angle between neighboring hexamers is a primary mechanism for the modulation of capsid stability. In addition, hexamer-pentamer interfaces were highly stable, suggesting that pentamers are likely not the locus of disassembly.

中文翻译：

---

IP6 和 PF74 通过调节六聚体-六聚体倾斜角度偏好影响 HIV-1 衣壳稳定性


HIV-1 衣壳是一种形状不规则的蛋白质复合物，包含病毒基因组和整合到宿主细胞基因组中所需的几种蛋白质。已知小分子，如类药物化合物 PF-3450074 （PF74） 和阴离子糖肌醇六磷酸酯 （IP6），会影响衣壳稳定性，尽管它们这样做的机制仍然未知。在这项研究中，我们采用原子分子动力学模拟来研究在中心孔 （IP6） 和 FG 结合位点 （PF74） 与六聚体结合的分子对衣壳寡聚体之间界面的影响。我们发现 IP6 辅因子将一对相邻的六聚体稳定在最平坦的构型中，而 PF74 引入了对中间倾斜角的强烈偏好。这些结果表明，相邻六聚体之间的倾斜角是调节衣壳稳定性的主要机制。此外，六聚体-五聚体界面高度稳定，表明五聚体可能不是反汇编的位点。