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Flap opening in HIV-1 protease simulated by 'activated' molecular dynamics
J R Collins1, S K Burt, J W Erickson
1Structural Biochemistry Program, Frederick Biomedical Supercomputing Center, PRI/DynCorp, National Cancer Institute - Frederick Cancer Research and Development Center, Maryland 21702-1201, USA.
Nature Structural Biology
|April 1, 1995
Summary
Activated molecular dynamics revealed HIV-1 protease flap opening mechanisms. A specific mutation (M46I) was found to stabilize the flaps in a closed state, potentially impacting drug resistance.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- HIV-1 protease is a key target for antiretroviral therapy.
- The enzyme's flap dynamics are crucial for its catalytic activity and substrate binding.
- Understanding flap opening is essential for designing effective inhibitors.
Purpose of the Study:
- To simulate and analyze the process of flap opening in HIV-1 protease using activated molecular dynamics.
- To investigate the conformational changes associated with flap opening.
- To examine the effect of the M46I mutation on flap stability.
Main Methods:
- Activated molecular dynamics simulations were employed.
- Harmonic constraints were applied to non-flap residues to initiate flap opening.
- Analysis of backbone torsion angles was performed to identify key residues involved in conformational changes.
Main Results:
- Simulations showed flap opening to a 25 Å gap within 200 ps.
- Conformational changes at Lys 45, Met 46, Gly 52, and Phe 53 were linked to flap opening.
- The M46I mutation was observed to stabilize the flaps in a closed conformation.
Conclusions:
- The study elucidates the mechanism of HIV-1 protease flap opening.
- The M46I mutation confers drug resistance by stabilizing the closed flap conformation.
- These findings provide insights into protease dynamics relevant to drug development.