Journal article
Energetics of Flap Opening in HIV‑1 Protease: String Method Calculations
The journal of physical chemistry. B, v 123(45), pp 9584-9591
14 Nov 2019
PMID: 31640343
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
HIV-1 protease (PR) is the viral protein responsible for virion maturation, and its mechanisms of action remain incompletely understood. PR is dimeric and contains two flexible, symmetry-related flaps, which act as a gate to inhibit access to the binding pocket and hold the polypeptide substrate in the binding pocket once bound. Wide flap opening, a conformational change assumed to be necessary for substrate binding, is a rare event in the closed and bound form. In this study, we use molecular dynamics (MD) simulations and advanced MD techniques including temperature acceleration and string method in collective variables to study the conformational changes associated with substrate unbinding of both wild-type and F99Y mutant PR. The F99Y mutation is shown via MD to decouple the closing of previously unrecognized distal pockets from substrate unbinding. To determine whether or not the F99Y mutation affects the energetic cost of wide flap opening, we use string method in collective variables to determine the minimum free-energy mechanism for wide flap opening in concert with distal pocket closing. The results indicate that the major energetic cost in flap opening is disengagement of the two flap-tip Ile50 residues from each other and is not affected by the F99Y mutation.
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Details
- Title
- Energetics of Flap Opening in HIV‑1 Protease: String Method Calculations
- Creators
- Jasmine M Gardner - Department of Chemistry - BMCCameron F Abrams - Dept. of Chemical and Biological Engineering
- Publication Details
- The journal of physical chemistry. B, v 123(45), pp 9584-9591
- Publisher
- American Chemical Society; Washington, DC
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:000497259800008
- Scopus ID
- 2-s2.0-85074896159
- Other Identifier
- 991014969873904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biophysics
- Chemistry, Physical