IP6 and PF74 affect HIV-1 Capsid Stability through Modulation of Hexamer-Hexamer Tilt Angle Preference.

Area of Science:

• Structural biology
• Virology
• Computational biophysics

Background:

• The human immunodeficiency virus type 1 (HIV-1) capsid is essential for viral replication, mediating nuclear entry and genome integration.
• Emerging therapeutics, like lenacapavir, target non-enzymatic viral proteins, highlighting the capsid as a drug target.
• Molecules such as inositolhexakisphosphate (IP6) and PF74 are known to affect capsid stability, but their precise mechanisms remain unclear.

Approach:

• Employed systematic atomistic simulations to investigate the impact of IP6 and PF74 on capsid oligomer dynamics.
• Compared the effects of IP6 (bound at the central pore) and PF74 (bound at the FG-binding site) on hexamers and pentamers.
• Analyzed the free energy profiles of inter-hexamer binding and angular deformations to assess structural flexibility.

Key Points:

• Neither IP6 nor PF74 significantly altered the free energy of binding between neighboring hexamers.
• Both molecules impacted the free energy profiles associated with angular deformations, affecting capsid curvature.
• IP6 stabilizes hexamers in flatter configurations, while PF74 favors intermediate tilt angles between hexamers.

Conclusions:

• HIV-1 capsid structural instability is a natural property modulated by small molecules binding to specific sites.
• IP6 and PF74 exhibit distinct effects on capsid flexibility despite potential similarities in protein-protein interactions.
• Findings provide a detailed model of HIV-1 capsid-small molecule interactions, guiding structure-based drug design and experimental strategies.