Viral infectivity factor (Vif) is an intrinsically disordered protein (IDP) utilized by HIV-1 to hijack host immune defenses. Vif binds to an E3 ubiquitin ligase complex composed of CBF-ß, Elongin B, Elongin C, and Cullin 5, which ubiquitinates proteins for proteasomal degradation. Within this VCBC (Vif, CBF-ß, ELOB, and ELOC) ligase complex, Vif acts as a substrate-binding protein for antiviral APOBEC3 proteins (A3s), resulting in their ubiquitination and degradation. The removal of A3s allows HIV-1 to replicate and spread. We investigated the cryogenic-EM structure of A3F, a member of the A3 family, bound to the HIV-Vif-A3F complex using molecular dynamics (MD) simulations to better understand the binding process and identify critical conformation for stabilization. Free energy analysis was run on both VCBC and VCBC-A3F MD simulations. We targeted a residue displaying a large free-energy difference for mutation. We ran preliminary simulations on this mutation, and principal component analysis (PCA) along with contact maps were employed to analyze its effect on binding. This approach allows us to better understand the molecular interactions between A3F and Vif and may guide the development of treatments to target and interrupt HIV-Vif-A3F binding, thus limiting HIV replication and spread.
Geiss et al. (Sun,) studied this question.