Infection of CD4+ T cells by macrophage-tropic HIV-1 strains involves interaction of viral gp120 with the host cell chemokine receptor CCR5. The principle neutralizing determinant (PND) of the V3-loop of the HIV-1 gp120 was investigated for its interaction with CCR5 by computational modeling methods at atomic resolution and electrostatic calculations to complement experimental findings. The study focused on the recognition step and examined possible peptide-peptide interactions between various PND-derived peptides from the V3-loop and the N-terminal (Nt) domain of CCR5. These recognition interactions are possible because of the complementary character of the spatial distribution of the predominantly positive electrostatic potentials of the PND-derived peptides and the predominantly negative electrostatic potential of the CCR5Nt domain. The CCR5Nt appears more amenable to interaction with the V3 peptides, than the other CCR5 extracellular domains (ECL), because of its length and the domination of its negative electrostatic potential. On the contrary, ECL2 possesses a predominantly positive electrostatic potential. There are positive patches in Nt and negative patches in ECL2, which, following the non-specific recognition of the V3-loop by CCR5 and with the expected local structural rearrangements to facilitate specific binding, may be contributing to the stabilization of the complex. A sequential two-step specific binding, involving different extracellular domains, is conceivable. Although the electrostatic potentials may play a role in a V3-CCR5 interaction, a more specific model cannot be derived in the absence of a three-dimensional structure of a gp120/CD4/CCR5 complex.

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