Does Antibody Stabilize the Ligand Binding in GP120 of HIV-1 Envelope Protein? Evidence from MD Simulation

CD4-mimetic HIV-1 entry inhibitors are small sized molecules which imitate similar conformational flexibility in gp120 as CD4 receptor, the mechanism of the conformational flexibility instigated by these small sized inhibitors, however, is little known. Likewise, the effect of the antibody on the function of these inhibitors is also less studied. In this study, we present a thorough inspection of the mechanism of the conformational flexibility induced by a CD4-mimetic inhibitor, NBD-557, using Molecular Dynamics Simulations and free energy calculations. Our result shows a functional importance of Asn239 in substrate instigated conformational dynamics in gp120. The MD simulations of Asn239Gly mutant provide a less dynamic gp120 in the presence of NBD-557 without incapacitating the binding enthalpy of NBD-557. The MD simulations of complex with the antibody clearly shows the enhanced affinity of NBD-557 due to the presence of the antibody which is in good agreement with experimental Isothermal Titration Calorimetry results (Biochemistry 2006, 45, 10973-10980).