Prediction of the Binding Mode between the Small Peptide Inhibitor EBR28 with Integrase through Molecular Modeling Methods

Human immunodeficiency virus type 1 (HIV-1) integrase (IN), which aids the integration of viral DNA into the host chromosome, is an essential enzyme in the lifecycle of this virus and also an important target for the study of anti-HIV drugs. Recently synthesized 12-mer EBR28 which was identified through the yeast two-hybrid system and could strongly bind to IN is one of the most potential small peptide leading compounds inhibiting IN binding to viral DNA. The binding mode of IN core domain and its peptide inhibitor EBR28 was investigated by using molecular docking and molecular dynamics (MD) simulation and confirmed with a semi-empirical binding free energy calculation method, i.e. MM-GBSA model. The results show that EBR28 binds to the interspace between alpha1 helix and alpha5 helix in the IN core domain mainly through hydrophobic interactions, which impedes the dimerization of the two IN monomers and inhibits IN binding to viral DNA in the end. The correlation between calculated and experimental binding free energies is very good (r = 0.88). All of the above simulation results agree well with experimental data, which provide us with some helpful information for designing anti-HIV small peptide drugs based on the structure of IN.