Structural Implications of HIV-1 Protease Subtype C Bound to Darunavir: A Molecular Dynamics Study.

In recent years, Human Immunodeficiency Virus (HIV) remains a significant global health challenge, with millions affected worldwide, particularly in Africa and sub-Saharan regions. Despite advances in antiretroviral therapies, the genetic variability of HIV, including different subtypes and drug-resistant strains, poses persistent obstacles in the development of universally effective treatments. This study focuses on the dynamics of HIV protease, a key enzyme in viral replication and maturation, particularly targeting subtype C and its double insertion (HL) variant L38HL, in the context of interaction with Darunavir (DRV), a second-generation nonpeptidic protease inhibitor approved by the FDA in 2006. Through molecular dynamics simulations, structural analyses, dynamic cross-correlation analyses, and binding energy calculations, we investigated differences in the binding of DRV to WT and L38HL HIV-1 protease. The findings highlight that the double insertion at the hinge induces variation in Φ and Ψ angles, leading to increased residue fluctuations, solvent-accessible surface area (SASA), and radius of gyration (Rg). This alters the overall structural compactness and the hydrophobic core crucial for drug binding. Subtle structural changes result in the loss of hydrogen bond interactions, reducing the binding energy of L38HL HIV-1 protease subtype C bound to DRV, leading to drug resistance.