Modeling and Analysis of HIV-1 Pol Polyprotein as a Case Study for Predicting Large Polyprotein Structures

Area of Science:

• Virology
• Structural Biology
• Drug Discovery

Background:

• Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV).
• Current HIV therapies target viral enzymes, but drug resistance is a growing concern due to rapid viral mutation.
• The HIV Gag-Pol polyprotein is a critical target for novel antiviral strategies.

Purpose of the Study:

• To investigate the molecular mechanism of HIV-1 integrase mutations (M50I and V151I) affecting Gag-Pol polyprotein processing.
• To develop a computational workflow for predicting the tertiary structure of the full-length HIV-1 Pol polyprotein.
• To establish a structural basis for understanding HIV-1 Pol autoprocessing and developing new drugs.

Main Methods:

• Utilized a computational workflow to predict the tertiary structure of the full-length HIV-1 NL4.3 Pol polyprotein.
• Validated the modeled structure against existing partial HIV-1 Pol structures (e.g., PDB ID: 7SJX).

Main Results:

• Generated the first full-length tertiary structure model of the HIV-1 NL4.3 Pol polyprotein dimer.
• The predicted structure demonstrates high quality, comparable to experimentally determined partial structures.
• The model provides insights into how specific mutations can inhibit Gag-Pol polyprotein maturation without affecting dimerization.

Conclusions:

• The developed workflow enables the prediction of large, complex protein structures, including the full-length HIV-1 Pol.
• The novel full-length Pol structure serves as a platform for studying viral polyprotein processing and designing new antiviral agents.
• This structural model can guide the development of next-generation HIV therapeutics to combat drug resistance.