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bioRxiv · 10.1101/2025.10.22.683870

Dimerization Mechanism of HIV-1 RNA Hairpins to Extended Duplex Structures

Mondal, D.·Habibullah, S.·Reddy, G.
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Abstract

Genomic RNA (gRNA) dimerization is essential for retroviral replication. In the gRNA of human immunodeficiency virus (HIV-1), the hairpin-like dimerization initiation sequence (DIS) forms a kissing-complex (KC) with the DIS sequence in another gRNA, which later converts into a stable extended-duplex (ED). Using coarse-grained simulations, we mapped the transition of HIV-1 DIS RNA hairpins (HPs) to ED and identified multiple intermediates beyond the KC. The KC has an anionic pocket stabilized through the condensation of Mg2+ ions. Hence, when only K+ ions are present at physiological levels, the HPs to ED transitions occur through a different dominant pathway devoid of the KC. We also observed purine base flipping near KC hydrogen bonds, revealing the population of a sub-ensemble of intermediates. The proposed dimerization mechanism of HPs to ED, along with the sub-ensemble of KC conformations and its anionic pocket, provides a strategic framework for designing specific retroviral drugs targeting this pathway. For Table of Contents Use Only O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/683870v1_ufig1.gif" ALT="Figure 1"> View larger version (94K): org.highwire.dtl.DTLVardef@2cb0f5org.highwire.dtl.DTLVardef@15c8d1org.highwire.dtl.DTLVardef@3321cborg.highwire.dtl.DTLVardef@efd30d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Mondal, D., Habibullah, S., Reddy, G.. 2025-10-22. Dimerization Mechanism of HIV-1 RNA Hairpins to Extended Duplex Structures. https://doi.org/10.1101/2025.10.22.683870

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