Inositol hexakisphosphates (IP₆) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP₆ increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP₆. We find that capsid hexamers and pentamers have differential binding modes for IP₆. Ligand density calculations show three sites of interaction with IP₆ including at a known capsid inhibitor binding pocket. Free energy calculations demonstrate that IP₆ preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP₆ in stabilizing and assembling the retroviral capsid.

六磷酸肌醇 (IP ₆ ) 是促进 HIV 成熟衣壳组装的细胞辅助因子。这些带负电的分子在分布于整个衣壳表面的孔的中心处配位正电的精氨酸环。动力学研究表明，IP ₆的结合使衣壳的稳定寿命增加了几个数量级，从几分钟到几小时。通过全原子分子动力学模拟，我们揭示了与 IP ₆复合的成熟衣壳异常高稳定性的机制。我们发现衣壳六聚体和五聚体对IP ₆具有不同的结合模式。配体密度计算显示与 IP ₆相互作用的三个位点，包括已知的衣壳抑制剂结合袋。自由能计算表明，IP ₆优先稳定五聚体而不是六聚体，以增强富勒烯的组装模式。这些结果阐明了 IP ₆在稳定和组装逆转录病毒衣壳中的分子作用。