(577e) Elucidating the Molecular Recognition of CXCR4 By a Dual Tropic HIV-1 gp120 V3 Loop Using Free Energy Calculations and Molecular Dynamics Simulations

The primary step of the human immunodeficiency virus type 1 (HIV-1) cell entry is the interaction of the viral envelope glycoprotein (comprising subunits gp41 and gp120) with the host leukocyte glycoprotein receptor, CD4, and the two chemokine receptors CXCR4 / CCR5 on the surface of host cells. The molecular recognition of CXCR4 or CCR5 by gp120 is mediated through the V3 loop, a fragment of gp120. The binding of the V3 loop to CXCR4 or CCR5 determines the cell tropism of HIV-1 and constitutes a key step prior to HIV-1 cell entry. Thus, elucidating the molecular recognition of CXCR4 by the V3 loop is important for understanding HIV-1 viral infectivity, tropism and designing HIV-1 inhibitors. We employed a comprehensive set of computational tools, predominantly based on free energy calculations and molecular dynamics (MD) simulations to investigate the molecular recognition of CXCR4 by a dual tropic V3 loop. We report the first V3 loop : CXCR4  complex structure, and our results are in remarkable agreement with experiments, as well as, reveal an abundance of specific intermolecular interactions contributing to the stability of the binding conformation. This work sheds light into the functional role of V3 loop and CXCR4 residues associated with HIV-1 gp120 activity, and therefore, it provides gateways for understanding HIV-1 viral infectivity, tropism, and designing novel anti-HIV-1 inhibitors of protein gp120.