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Energetics of Flap Opening in HIV-1 Protease: String Method Calculations
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Drexel Univ, Dept Chem & Biol Engn, 3141 Chestnut St, Philadelphia, PA 19104 USA.ORCID iD: 0000-0002-6399-8504
Drexel Univ, Dept Chem & Biol Engn, 3141 Chestnut St, Philadelphia, PA 19104 USA.ORCID iD: 0000-0002-1240-0816
2019 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 123, no 45, p. 9584-9591Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2019. Vol. 123, no 45, p. 9584-9591
National Category
Physical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-398563DOI: 10.1021/acs.jpcb.9b08348ISI: 000497259800008PubMedID: 31640343OAI: oai:DiVA.org:uu-398563DiVA, id: diva2:1376371
Funder
NIH (National Institute of Health), R01GM100472Available from: 2019-12-09 Created: 2019-12-09 Last updated: 2019-12-09Bibliographically approved

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Gardner, Jasmine M.

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