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Published on: September 15, 2010
The influence of macromolecular crowding on HIV-1 protease internal dynamics
David D L Minh1, Chia-en Chang, Joanna Trylska
1Department of Chemistry & Biochemistry, Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093-0365, USA. dminh@mccammon.ucsd.edu
Insights
Macromolecular crowding significantly reduces HIV-1 protease flap opening, impacting enzyme activity. This finding suggests crowding plays a key role in the viral life cycle.
Area of Science:
- Biochemistry
- Molecular Biology
- Biophysics
Background:
- High macromolecular concentrations, or crowded conditions, affect molecular processes like diffusion, protein folding, and stability.
- Macromolecular crowding is prevalent in cellular environments and influences biological functions.
Purpose of the Study:
- To model the effect of macromolecular crowding on the internal dynamics of HIV-1 protease.
- To investigate how crowding influences the opening and closing of protease flaps, which are crucial for its catalytic mechanism.
Main Methods:
- Brownian dynamics simulations were employed to model HIV-1 protease dynamics.
- The simulations compared the behavior of the protease at low and high (close-packed) concentrations of repulsive crowding agents.
Main Results:
- Close-packed concentrations of crowding agents significantly reduced the fraction of time HIV-1 protease flaps remained open compared to low concentrations.
- The internal dynamics of the protease were altered by the presence of crowding agents.
Conclusions:
- Macromolecular crowding substantially impacts HIV-1 protease flap dynamics.
- Crowding likely influences in vivo enzyme activity and may regulate the viral life cycle.
Abstract:
High macromolecular concentrations, or crowded conditions, have been shown to affect a wide variety of molecular processes, including diffusion, association and dissociation, and protein folding and stability. Here, we model the effect of macromolecular crowding on the internal dynamics of a protein, HIV-1 protease, using Brownian dynamics simulations. HIV-1 protease possesses a pair of flaps which are postulated to open in the early stages of its catalytic mechanism. Compared to low concentrations, close-packed concentrations of repulsive crowding agents are found to significantly reduce the fraction of time that the protease flaps are open. Macromolecular crowding is likely to have a major effect on in vivo enzyme activity, and may play an important regulatory role in the viral life cycle.
