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Flexibility of Monomeric and Dimeric HIV-1 Protease

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Department of Chemical Physics, School of Chemistry, Tel Aviv University, Tel Aviv 69978, Israel, and Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Cite this: J. Phys. Chem. B 2003, 107, 13, 3068–3079
Publication Date (Web):March 12, 2003
Copyright © 2003 American Chemical Society

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    The flexibility and stability of both monomeric and dimeric HIV-1 PR were explored by 100 ns implicit solvent molecular dynamics simulation at 350 K with the aim to correlate the monomer stability with the dimerization mechanism. The principal component analysis (PCA) was applied to visualize the available regions in the conformational space of the two HIV-1 PR forms, to compare their structural diversity and to map the bottom of their underlying energy landscapes. It was found that whereas the flap tips (residues 45−55) are flexible and adopt close and open conformations in both monomeric and dimeric forms, the N- and C-termini (residues 1−4 and 96−99, respectively), which constitute the interface between the two subunits, are flexible only in the monomer. The different flexibility of the monomeric and dimeric HIV-1 PR is reflected in the different topography of their underlying energy landscape. Although the bottom of the monomer energy landscape is broad and rough, that of the dimer is narrower, deeper, and smoother, reflecting the enhanced flexibility of the monomer and the stabilizing interactions between the dimer subunits. Accordingly, blocking one or both terminals may prevent the formation of the active site. Despite the different flexibility of the termini in the monomeric and dimeric HIV-1 PR, their secondary structure contents are similar. The partial stability of the monomer together with the flexibility of its termini suggest that the HIV-1 PR is not a two-state dimer, as indicated by equilibrium denaturation experiments, but a three-state dimer with a marginally stable monomeric intermediate. This involves the swapping of the flexible termini across the two chains to form the dimer interface.

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     Abbreviations:  HIV-1, human immunodeficiency virus type 1; PR, protease; PCA, principal component analysis; RMSD, root-mean-square deviation; MD, molecular dynamics.


    In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

     Tel Aviv University.


     Current address:  Department of Chemistry and Physics, University of California at San Diego, 9500 Gilman drive, La Jolla, CA 92093-0371.

     University of Zurich.

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