The role of mutations at codons 32, 47, 54, and 90 in HIV-1 protease flap dynamics.

Autor:	Chordia P; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.; Department of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan, USA., Dewdney TG; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA., Keusch B; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA., Kuiper BD; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA., Ross K; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA., Kovari IA; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA., MacArthur R; Department of Infectious Diseases, Wayne State University School of Medicine, Detroit, Michigan, USA., Salimnia H; Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA., Kovari LC; Department of Biochemistry and Molecular Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
Jazyk:	angličtina
Zdroj:	Discoveries (Craiova, Romania) [Discoveries (Craiova)] 2014 Dec 31; Vol. 2 (4), pp. e27. Date of Electronic Publication: 2014 Dec 31.
DOI:	10.15190/d.2014.19
Abstrakt:	Treatment of Human Immunodeficiency Virus remains challenging due to the emergence of drug resistant strains under the selective pressure produced by standard anti-retroviral therapy. To explore the structural mechanisms of drug resistance, we performed 40 ns molecular dynamics simulations on three multi-drug resistant HIV-1 protease clinical isolates from patients attending an infectious diseases clinic in Detroit, MI. We identify a novel structural role for the I47V, V32I, I54M and L90M major resistance mutations in flap opening and closure of MDR-PR isolates. Our studies suggest I47V is involved in flap opening and the interaction between I47V and V32I tethers the flaps to the active site. Also, I54M and L90M may be responsible for asymmetric movement of the protease flaps. These findings can be utilized to improve drug design strategies against MDR HIV-1 PR variants. Competing Interests: Conflict of interests: The authors report no conflict of interest. (Copyright © 2014, Applied Systems.)
Databáze:	MEDLINE
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