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

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 subensemble of intermediates. The proposed dimerization mechanism of HPs to ED, along with the subensemble of KC conformations and its anionic pocket, provides a strategic framework for designing specific retroviral drugs targeting this pathway.