HIV-1 protease substrate binding and product release pathways explored with coarse-grained molecular dynamics

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Chemistry

Background:

• HIV-1 protease is a key target for antiretroviral therapy.
• Understanding substrate interactions is crucial for drug design.
• Previous models studied flap dynamics but not substrate incorporation.

Purpose of the Study:

• To investigate the mechanism of peptide substrate binding and product release in HIV-1 protease.
• To extend a coarse-grained model to include substrate interactions.
• To elucidate the role of protein flexibility in ligand dynamics.

Main Methods:

• Extended coarse-grained model force field.
• Molecular and Langevin dynamics simulations.
• Analysis of protein-substrate interactions and dynamics.

Main Results:

• Flap opening is essential for peptide substrate binding to HIV-1 protease.
• Protease-substrate interactions modulate flap opening dynamics.
• Product release occurs without flap opening, via sliding.
• Specific protein turns (17- and 39-) exhibit high fluctuations, correlated with substrate motion.

Conclusions:

• Protein flexibility, particularly flap dynamics, plays a critical role in ligand binding and release.
• The study provides mechanistic insights into HIV-1 protease function.
• The extended model facilitates future studies on enzyme-substrate interactions.