Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease

Area of Science:

• Biochemistry and enzymology
• Computational chemistry
• Molecular dynamics

Background:

• Enzyme dynamical flexibility is crucial for understanding biological reaction mechanisms.
• HIV-1 protease is a key target for antiviral therapies, and its reaction mechanism is of significant interest.

Purpose of the Study:

• To investigate the convergence of activation free energy for the initial reaction step catalyzed by HIV-1 protease.
• To provide evidence for mechanistic divergence in HIV-1 protease, with multiple reaction pathways contributing to the catalytic step.

Main Methods:

• Utilized quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations.
• Employed four distinct initial conformations from a previous study to assess reaction barriers.
• Analyzed the activation free energy and identified contributing mechanistic pathways.

Main Results:

• Despite extensive simulations, activation free energies varied by 5.0 kcal/mol across different conformations.
• Confirmed mechanistic divergence, with two distinct pathways exhibiting similar energy barriers.
• Identified an active-site water molecule as a potential influencer of the reaction pathway.

Conclusions:

• Enzyme flexibility significantly influences reaction pathways and energy landscapes.
• HIV-1 protease exhibits mechanistic divergence, suggesting complex catalytic strategies.
• Water molecules play a critical role in modulating enzyme reaction mechanisms.