2026-10-13T20:23:30Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33942920 2026-09-19T15:19:19Z category_1 category_4 category_915 category_12 category_14 category_873 category_734 category_132 category_135 portal_63 item_type_2 month_year_09_2026

Inositol Hexakisphosphate Promotes Open Pore State in HIV Capsid Protein Lattice by Reconfiguring Subunit Contacts Yari Katar Knelissen (25076312) Judith Escrig (19750275) Amanda C. Macke (15333900) Sruthi Sudhakar (12060054) Santos Domínguez-Zotes (19750281) Sourav Maity (3396374) Mauricio G. Mateu (187214) Juan R. Perilla (2638567) Wouter H. Roos (2149699) Alejandro Valbuena (161932) Biophysics Biochemistry Physical Sciences not elsewhere classified Cell Biology Molecular Biology Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Infectious Diseases Computational Biology unified mechanistic framework two major states reconfiguring subunit contacts mechanically stabilized nanomaterial fuel reverse transcription averaged structural models intersubunit contact reconfiguration individual hexamer pores identifying dynamic transitions induced pore conformations central pore delimited results establish ip6 ip6 markedly enhances intersubunit interactions individual hexamers dynamic behavior pore entrance pore conformation viral replication viral genome real time proviral regulator poorly understood open state nucleoside triphosphates modulates translocation mechanical resilience mechanical fatigue lack information coordinated rearrangement asynchronous motions The mature human immunodeficiency virus (HIV-1) capsid is composed of approximately 250 capsid protein hexamers, each containing a central pore delimited by a β-hairpin and an α-helix from each monomer. The cellular metabolite inositol hexakisphosphate (IP6) binds this pore and modulates translocation of nucleoside triphosphates into the capsid, where they fuel reverse transcription of the viral genome. However, the mechanism by which IP6 modulates the pore conformation is poorly understood. Averaged structural models of the HIV-1 capsid protein lattice have shed some light on this mechanism but lack information on the dynamic behavior of individual hexamers that could provide deeper mechanistic insights. Here we visualized in real time by high-speed atomic force microscopy the asynchronous motions of individual hexamer pores in the presence or absence of IP6, identifying dynamic transitions between two major states. Quantitative analysis enabled estimation of the IP6-induced pore conformations and populations. Constant-pH molecular dynamics simulations further reveal that IP6 induces contact rewiring at the pore entrance, stabilizing the open state through coordinated rearrangement of intersubunit interactions. Consistently, mechanical fatigue assays show that IP6 markedly enhances the resistance of the capsid lattice to mechanical fatigue, revealing its role as a mechanically stabilized nanomaterial. Together, these results establish IP6 as a proviral regulator that couples nanoscale pore dynamics, intersubunit contact reconfiguration, and mechanical resilience of the HIV-1 capsid, providing a unified mechanistic framework for its role in viral replication. 2026-09-19T00:00:00Z Dataset Media 10.1021/acsnano.6c07706.s002 https://figshare.com/articles/media/Inositol_Hexakisphosphate_Promotes_Open_Pore_State_in_HIV_Capsid_Protein_Lattice_by_Reconfiguring_Subunit_Contacts/33942920 CC BY-NC 4.0