Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop

Abstract

The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13-21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics.

Figure 1. HIV-1 gp120 V3 loop : CCR5 Complex Structure;

Molecular graphics image of the entire simulation system corresponding to the complex with the lowest average binding free energy. The V3 loop is shown in tube and transparent surface representation in red color, and the residue moiety 16–20 is shown in fat tube representation. The CCR5 is shown in cartoon representation, and the coloring used for different protein domains is as follows: (i) N-terminal domain is colored in blue, (ii) Transmembrane helix 1 (TH1) is colored in green; (iii) Intracellular loop 1 (ICL1) is colored in light gray; (iv) TH2 is colored in purple, (v) Extracellular loop 1 (ECL1) is colored in light gray; (vi) TH3 is colored in yellow; (vii) ICL2 is colored in light gray; (viii) TH4 is colored in gray; (ix) ECL2 is colored in ochre; (x) TH5 is colored in pink; (xi) ICL3 is colored in light gray; (xii) TH6 is colored in cyan; (xiii) ECL3 is colored in lime; (xiv) TH7 is colored in orange; (xv) C-terminal domain is colored in light gray. The N-terminal Cα atom of CCR5 is shown in a small van der Waals sphere and the V3 loop disulfide bridge is shown in fat transparent licorice representation. The definition of CCR5 and V3 loop domains is presented in Information S4.

Figure 2. Important Intermolecular Polar Interactions;

Molecular graphics image of important polar interactions corresponding to the complex with the lowest average binding free energy. The figure shows the salt bridges and specific important hydrogen bonds. The V3 loop is shown in tube and in red color, and the residue moiety 16–20 is shown in fat tube representation. The CCR5 is shown in light gray transparent tube representation. The salt bridge and hydrogen bonds are denoted in dashed lines and the participating V3 loop and CCR5 residue moieties are shown in licorice; V3 loop and CCR5 residues are annotated in red and black, color respectively. Hydrogen atoms are omitted for clarity, and the V3 loop disulfide bridge is shown in fat transparent licorice representation.

Figure 3. Intermolecular Interaction Free Energies of V3 loop Residues in Complex with CCR5/CXCR4;

Average intermolecular interaction free energies (y-axis) of V3 loop residues (x-axis). The intermolecular interaction free energies for every V3 loop residue are summed up for all interacting residues of CCR5 (first bar per residue) and CXCR4 (second bar per residue). The polar contribution is denoted in red and green color, for CCR5 and CXCR4, respectively, and the non-polar contribution is denoted in blue and black color, for CCR5 and CXCR4, respectively. The total interaction free energy of each V3 loop residue corresponds to the sum of polar and non-polar contributions.