Computational Model of the HIV-1 Subtype A V3 Loop: Study on the Conformational Mobility for Structure-Based Anti-AIDS Drug Design

The V3 loop of the HIV-1gp120 glycoprotein presenting 35-residue-long, frequently glycosylated, highly variable, and disulfide bonded structure plays the central role in the virus biology and forms the principal target for neutralizing antibodies and the major viral determinant for co-receptor binding. Here we present the computer-aided studies on the 3D structure of the HIV-1 subtype A V3 loop (SA-V3 loop) in which its structurally inflexible regions and individual amino acids were identified and the structure-function analysis of V3 aimed at the informational support for anti-AIDS drug researches was put into practice. To this end, the following successive steps were carried out: (i) using the methods of comparative modeling and simulated annealing, the ensemble of the low-energy structures was generated for the consensus amino acid sequence of the SA-V3 loop and its most probable conformation was defined basing on the general criteria widely adopted as a measure of the quality of protein structures in terms of their 3D folds and local geometry; (ii) the elements of secondary V3 structures in the built conformations were characterized and careful analysis of the corresponding data arising from experimental observations for the V3 loops in various HIV-1 strains was made; (iii) to reveal common structural motifs in the HIV-1 V3 loops regardless of their sequence variability and medium inconstancy, the simulated structures were collated with each other as well as with those of V3 deciphered by NMR spectroscopy and X-ray studies for diverse virus isolates in different environments; (iv) with the object of delving into the conformational features of the SA-V3 loop, molecular dynamics trajectory was computed from its static 3D structure followed by determining the structurally rigid V3 segments and comparing the findings obtained with the ones derived hereinbefore; and (v) to evaluate the masking effect that can occur due to interaction of the SA-V3 loop with the two virtual molecules constructed previously by tools of computational modeling and named FKBP and CycA peptides, molecular docking of V3 with these molecules was implemented and inter-atomic contacts appearing in the simulated complexes were analyzed to specify the V3 stretches keeping in touch with the ligands. As a matter of record, V3 segments 3-7, 15-20, and 28-32 containing the highly conserved and biologically meaningful residues of gp120 were shown to retain their 3D main chain shapes in all the cases of interest presenting the forward-looking targets for anti-AIDS drug researches. From the data on molecular docking, synthetic analogs of the CycA and FKBP peptides were suggested being suitable frameworks for making a reality of the V3-based anti-HIV-1 drug projects.