Comparison of Newly Assembled Full Length HIV-1 Integrase With Prototype Foamy Virus Integrase: Structure-Function Prospective

Abstract

Background: Drug design against human immunodeficiency virus type 1 (HIV-1) integrase through its mechanistic study is of great interest in the area in biological research. The main obstacle in this area is the absence of the full-length crystal structure for HIV-1 integrase to be used as a model. A complete structure, similar to HIV-1 of a prototype foamy virus integrase in complex with DNA, including all conservative residues, is available and has been extensively used in recent investigations.

Objectives: The aim of this study was to determine whether the above model is precisely representative of HIV-1 integrase. This would critically determine the success of any designed drug using the model in deactivation of integrase and AIDS treatment.

Materials and methods: Primarily, a new structure for HIV-1 was constructed, using a crystal structure of prototype foamy virus as the starting structure. The constructed structure of HIV-1 integrase was simultaneously simulated with a prototype foamy virus integrase on a separate occasion.

Results: Our results indicate that the HIV-1 system behaves differently from the prototype foamy virus in terms of folding, hydration, hydrophobicity of binding site and stability.

Conclusions: Based on our findings, we can conclude that HIV-1 integrase is vastly different from the prototype foamy virus integrase and does not resemble it, and the modeling output of the prototype foamy virus simulations could not be simply generalized to HIV-1 integrase. Therefore, our HIV-1 model seems to be more representative and more useful for future research.

Keywords: Human Immunodeficiency Virus Type-1; Integrase; Molecular Dynamic Simulation; Prototype Foamy Virus.

Figure 1.. The Sequence of Wild Type HIV-1 Integrase in FASTA Format

A, Wild-type HIV-1 integrase sequence in FASTA format obtained from the http://www.bioafrica.net/ website; B, sequence alignment results for wild-type HIV-1 and PFV integrase obtained from the http://fasta.bioch.virginia.edu/ Server.

Figure 2.. Root Mean Square Displacement

A, Root mean square displacement plot of HIV-1 and prototype foamy virus integrase backbone against their initial state obtained at 37°C and one atmospheric pressure in SPCE water box; B, root mean square displacement plot of DNA of HIV-1 and prototype foamy virus integrase-DNA complex against their initial state obtained at 37°C and one atmospheric pressure in SPCE water box and shows the RMSD progression of complexes of DNA with HIV-1 and PFV in comparison to their initial state.

Figure 3.. show Root Mean Square Fluctuation (RMSF)

A, Root mean square displacement plot of prototype foamy virus integrase obtained for 10 ns Simulation at 37°C and one atmospheric pressure in SPCE water box; B, root mean square displacement Plot of HIV-1 Integrase Obtained for 10 ns simulation at 37°C and one atmospheric pressure in SPCE water box; C, average root mean square displacement for catalytic residues of prototype foamy virus (Residues 120 - 282) and HIV-1 (Residues 50 - 212) calculated from data of Figure 4 A and B as average ± SD (P < 0.05)

Figure 4.. Hydrophobic Accessible Area (ASA) Curve of HIV-1 and Prototype Foamy Virus Integrase Changes During 10 ns Period of Simulation at 37°C and One Atmospheric Pressure, in the Presence of SPCE Water Box

Figure 5.. Graphic Representation of DNA Binding Site

A, Graphic representation of DNA binding site of HIV-1 integrase before (left) and after (right) simulation showing the movement of the 3'-dA through the binding site cleft obtained from 10 ns simulation at 37°C and one atmospheric pressure, in the presence of SPCE water box; B, Graphic representation of DNA binding site of PFV integrase before (left) and after (right) simulation showing the situation of 3'-dA and magnesium ions of A and B sites obtained from 10 ns simulation at 37°C and one atmospheric pressure, in the presence of SPCE water box.