Structural elucidation and molecular dynamics study targeting the viral surface glycoproteins against HIV-2 infection

Abstract

Introduction: The acquired immunodeficiency syndrome (AIDS) is the culmination of the infection by the human immunodeficiency viruses upon destruction of CD4+ lymphocytes of the host [1]. The efficacy of the available antiretroviral drugs is very limited against HIV-2 and, most importantly, none of the current drugs effectively prevents entry into the cells. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry [2,3]. The discovery of multiple new hit compounds that can be used as useful starting points towards drug candidates for HIV-1 and HIV-2 therapy is the main goal of this work. The glycoproteins gp120 and gp125 are critical to the receptors recognition and internalization of viral material into the cell. The study aimed to assess if the modulation of the glycoproteins activity can lead to the disturbance of the entry viral mechanism.

Materials and methods: Until now, it has been marked by the use of computational techniques to study the viral surface glycoproteins as potential drug targets against HIV-1 and HIV-2 infections. A 3D structure of HIV-2ROD gp125 was generated by homology modelling, using MOE2016 and MODELLER 9v19. Additionally, to disclose the importance of the main structural features and compare with experimental results, 3D-models of six V3 mutants were also generated using the C2V3C3 domain. Additionally, molecular dynamics is being performed, using Gromacs 2006.3, in order to better characterize this protein and disclose its the biological dynamic behaviour. The structures to use in molecular dynamic simulations were prepared using MOE 2016.0802 software and further exported as PDB files.

Results: It is primordial to understand the structural behavior of these domains inserted in the main structure. These mutations revealed selectively impact in the behaviour of the protein.

Structurally, the mutations studied leads to a loss of aromatic features, very important for the establishment of π-π interactions, which could induce a structural preference by a specific coreceptor.

Discussion and conclusions: In the absence of a crystallographic structure of HIV-2 envelope gp125 comprising variable domains, computer aided modulation is crucial to identify structural features in the variable regions that correlate with HIV-2 tropism and susceptibility to neutralization, highly associated with the mutated residues. These new insights into the structure-function relationship will help in the design of better models and into the following of the design of new small molecules capable of use under the proposal presented inhibit the attachment and binding of HIV with host cells mediated by the envelope surface glycoproteins.

Acknowledgements

Fundação para a Ciência e a Tecnologia for PhD Grant SFRH/BD/100643/2014 of Patrícia Serra and UID/DTP/04138/2013.