Computational Refinement and Validation Protocol for Proteins with Large Variable Regions Applied to Model HIV Env...

Area of Science:

• Structural biology
• Virology
• Computational modeling

Background:

• The envelope glycoprotein gp120 of Human Immunodeficiency Virus type 1 (HIV-1) is crucial for viral entry.
• Its variable regions present structural challenges, hindering detailed analysis.
• Understanding gp120 structure is key to developing effective HIV-1 therapies.

Purpose of the Study:

• To generate a comprehensive structural model of HIV-1 gp120.
• To analyze the complex of gp120 with CD4 and antibody 17b, including variable regions.
• To investigate the conformational dynamics of gp120 variable loops.

Main Methods:

• A computational protocol integrating cryo-electron microscopy (EM) maps and atomic-resolution core structures.
• Analysis of binding interactions and stereochemical/energetic favorability.
• Comparison of loop arrangements with existing gp120-antibody complexes.

Main Results:

• A novel, stereochemically favorable model of the gp120-CD4-17b complex was produced.
• The model demonstrates excellent fit with cryo-EM data (EMD: 5020) and expected binding interfaces.
• A potential motion of the V1V2 loop towards CD4 was identified, away from the CCR5 binding site.

Conclusions:

• The developed model provides new insights into the structural plasticity of HIV-1 gp120.
• The CD4-bound state of the V1V2 loop may not be optimal for binding multiple neutralizing antibodies.
• This structural understanding can inform the design of novel HIV-1 inhibitors.