Identification of a Novel Druggable Pocket in the HIV-1 gp120 C5 Domain at the Conformational Relay Junction

HIV-1 entry requires a conformational relay that transmits the receptor-engagement signal to membrane fusion activation, yet no approved drug targets this transmission step. Here I report a novel druggable pocket in the gp120 C5 domain (Arg465–Arg472, sequence RPGGGDMR) at this relay junction, identified through computational analysis of the gp120–CD4–CCR5 ternary complex (PDB 6MEO, 3.9 Å cryo-EM). The motif is 100% conserved across 360 solved gp120 structures and untouched by all 28 known entry-inhibitor resistance mutations. The pocket passes all five Halgren druggability criteria, and molecular docking of BMS-626529 yields −6.81 kcal/mol across a 20-frame MD ensemble. Half-microsecond simulations of four independent SOSIP trimer structures confirm the pocket as a conformational anchor: sub-2 Å internal RMSD, 0th RMSF percentile in three of four structures, kinematically decoupled from global backbone dynamics. Free energy perturbation reveals selective binding to the pre-CD4 conformation (ΔG = −4.03 kcal/mol) with strong negative allosteric coupling to CD4 engagement (ΔΔG = +3.95 kcal/mol), establishing a conformational selection mechanism. Umbrella sampling yields a ~7–8 kcal/mol PMF barrier consistent with the relay signal magnitude. This deposit contains the complete manuscript (PDF, LaTeX source, and Markdown), all analysis scripts (108), raw computational results (67 JSON files), and simulation parameters. Molecular dynamics trajectory data (~67 GB) is available via the companion download portal at https://hiv1-relay-data.jretting.workers.dev. GitHub repository: https://github.com/jonretting/gp120-relay-supplementary