A Molecular Dynamics Simulation of Peptide-Triazole HIV Entry Inhibitor Binding to gp120 Hydrophobic Core

The envelope spike on HIV surface is a non-covalent trimer of gp120 and gp41 dimers; with gp120 responsible for binding to the CD4 receptor and the mandatory coreceptor, CCR5 or CXCR4. Blocking the gp120-CD4 or gp120-coreceptor interaction can block viral entry and infection. The HNG family of peptides (sequence RINNIXWSEAMM, X= derivatized azidoproline) is a promising class of dual-site entry inhibitors thought to allosterically inhibit the binding process and trap the flexible gp120 molecule in an inactive state. To date, there have been no reports on the structure of the peptide or the peptide/gp120 complex. Here we have used Molecular Dynamics to develop a docking model in which the peptide binds in a tripartite fashion, preventing the formation of the bridging sheet in gp120, which is necessary for coreceptor attachment and initiation of entry. The protein undergoes significant induced fit conformational changes involving movement of large loops which allows the peptide to bind tightly. Our model is consistent with experimental observations on the peptide footprint on gp120, pointing to a hydrophobic core underneath the bridging sheet and close to the F43 pocket as the putative binding site. Our results provide an explanation for why the stereochemistry of the triazole moiety on the proline is important for peptide function, in addition to explaining the inactivity of D-tryptophan in the sequence. Furthermore, saturation transfer difference (STD) NMR experiments point to the I-X-P hydrophobic center on the peptide as the central contact point in the complex, which is consistent with the peptide pose proposed in MD studies. Our model may provide a unique basis for rational design of allosteric entry inhibitors of HIV and ultimately small molecule inhibitors of viral entry.