Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Disclosure of Conserved Structural Motifs in the HIV-1 Third Variable (V3) Loop by Comparative Analysis of 3D V3 Structures for Different Virus Subtypes
The V3 loop on gp120 from HIV-1 is a focus of many research groups involved in anti-AIDS drug development because this region of the protein is the principal target for neutralizing antibodies and determines the preference of the virus for T-lymphocytes or primary macrophages. Although the V3 loop is a promising target for anti-HIV-1 drug design, its high sequence variability is a major complicating factor. Nevertheless, the occurrence of highly conserved residues within the V3 loop allows one to suggest that they may preserve their conformational states in different HIV-1 strains and, therefore, should be promising targets for designing new anti-HIV drugs. In this connection, the issue of whether these conserved amino acids may help to keep the local protein structure and form the structurally rigid segments of V3 exhibiting the HIV-1 vulnerable spots is very relevant. One of the plausible ways to answer this question consists of examining the V3 structures for their consensus sequences corresponding to the HIV-1 group M subtypes responsible for the AIDS pandemic followed by disclosing the patterns in the 3D arrangement of the variable V3 loops. Because of the deficiency of experimental data on the V3 structures, these studies may be performed by homology modeling using the high-resolution X-ray and NMR-based V3 models as the templates.
In this work, the 3D structural models for the consensus amino-acid sequences of the V3 loops from the HIV-1 subtypes A, B, C, and D were generated by bioinformatics tools to reveal common structural motifs in this functionally important portion of the gp120 envelope protein. To this effect, the most preferable 3D structures of V3 were computed by homology modeling and simulated annealing methods and compared with each other, as well as with those determined previously by X-ray diffraction and NMR spectroscopy. Besides, the simulated V3 structures were also exposed to molecular dynamics computations, the findings of which were analyzed in conjunction with the data on the conserved elements of V3 that were obtained by collation of its static models.
As a matter of record, despite the high sequence mutability of the V3 loop, its segments 3-7, 15-20 and 28-32 were shown to form the structurally invariant sites, which include amino acids critical for cell tropism. Moreover, the biologically meaningful residues of the identified conserved stretches were also shown to reside in β-turns of the V3 polypeptide chain. In this connection, these structural motifs were suggested to be used by the virus as docking sites for specific and efficacious interactions with receptors of macrophages and T-lymphocytes. Therefore, the structurally invariant V3 sites found here represent potential HIV-1 weak points most suitable for therapeutic intervention.
In the light of the findings obtained, the strategy for anti-HIV-1 drug discovery aimed at the identification of co-receptor antagonists that are able to efficiently mask the structural motifs of the V3 loop, which are conserved in different virus subtypes, is highly challenging. To overcome this problem, an integrated computational approach involving theoretical procedures, such as homology modeling, molecular docking, molecular dynamics, QSAR modeling and free energy calculations, should be of great assistance in the design of novel, potent and broad antiviral agents. For some of the details of the methodologies of current drug designs employed here please consult the full length research articles (1-4).
This study was supported by grants from the Union State of Russia and Belarus (scientific program SKIF-GRID; № 4U-S/07-111), as well as from the Belarusian Foundation for Basic Research (project X10-017).
Alexander M. Andrianov1
1Institute of Bioorganic Chemistry
National Academy of Sciences of Belarus
Kuprevich Street 5/2
220141 Minsk, Republic of Belarus