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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
https://doi.org/10.1021/jp0219956
Copyright © 2003 American Chemical Society

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    Abstract

    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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    3. Sérgio Filipe Sousa, Bruno Tamames, Pedro Alexandrino Fernandes, and Maria João Ramos . Detailed Atomistic Analysis of the HIV-1 Protease Interface. The Journal of Physical Chemistry B 2011, 115 (21) , 7045-7057. https://doi.org/10.1021/jp200075s
    4. Kitiyaporn Wittayanarakul,, Ornjira Aruksakunwong,, Pornthep Sompornpisut,, Vannajan Sanghiran-Lee,, Vudhichai Parasuk,, Surapong Pinitglang, and, Supot Hannongbua. Structure, Dynamics and Solvation of HIV-1 Protease/Saquinavir Complex in Aqueous Solution and Their Contributions to Drug Resistance:  Molecular Dynamic Simulations. Journal of Chemical Information and Modeling 2005, 45 (2) , 300-308. https://doi.org/10.1021/ci049784g
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    7. Mohd Ahsan, Chinmai Pindi, Sanjib Senapati. Mechanism of darunavir binding to monomeric HIV-1 protease: a step forward in the rational design of dimerization inhibitors. Physical Chemistry Chemical Physics 2022, 24 (11) , 7107-7120. https://doi.org/10.1039/D2CP00024E
    8. Marzieh Ajamgard, Jaber Jahanbin Sardroodi, Alireza Rastkar Ebrahimzadeh, Mahrokh Rezaei Kamelabad. Molecular dynamics simulation study of gold nanosheet as drug delivery vehicles for anti-HIV-1 aptamers. Computational Biology and Chemistry 2021, 95 , 107595. https://doi.org/10.1016/j.compbiolchem.2021.107595
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    10. Idowu Kehinde, Pritika Ramharack, Manimbulu Nlooto, Michelle Gordon. The pharmacokinetic properties of HIV-1 protease inhibitors: A computational perspective on herbal phytochemicals. Heliyon 2019, 5 (10) , e02565. https://doi.org/10.1016/j.heliyon.2019.e02565
    11. Kavitha Kadirvelu, Nishter Nishad Fathima. Self-assembly of keratin peptides: Its implication on the performance of electrospun PVA nanofibers. Scientific Reports 2016, 6 (1) https://doi.org/10.1038/srep36558
    12. Fabio Pietrucci, Attilio Vittorio Vargiu, Agata Kranjc. HIV-1 Protease Dimerization Dynamics Reveals a Transient Druggable Binding Pocket at the Interface. Scientific Reports 2016, 5 (1) https://doi.org/10.1038/srep18555
    13. Chris A. Kieslich, Phanourios Tamamis, Yannis A. Guzman, Melis Onel, Christodoulos A. Floudas, . Highly Accurate Structure-Based Prediction of HIV-1 Coreceptor Usage Suggests Intermolecular Interactions Driving Tropism. PLOS ONE 2016, 11 (2) , e0148974. https://doi.org/10.1371/journal.pone.0148974
    14. Mary A. Rohrdanz, Wenwei Zheng, Cecilia Clementi. Discovering Mountain Passes via Torchlight: Methods for the Definition of Reaction Coordinates and Pathways in Complex Macromolecular Reactions. Annual Review of Physical Chemistry 2013, 64 (1) , 295-316. https://doi.org/10.1146/annurev-physchem-040412-110006
    15. Kuntida Kitidee, Sawitree Nangola, Sudarat Hadpech, Witida Laopajon, Watchara Kasinrerk, Chatchai Tayapiwatana. A drug discovery platform: A simplified immunoassay for analyzing HIV protease activity. Journal of Virological Methods 2012, 186 (1-2) , 21-29. https://doi.org/10.1016/j.jviromet.2012.07.022
    16. Aditi Borkar, Manoj Kumar Rout, Ramakrishna V. Hosur. Denaturation of HIV-1 Protease (PR) Monomer by Acetic Acid: Mechanistic and Trajectory Insights from Molecular Dynamics Simulations and NMR. Journal of Biomolecular Structure and Dynamics 2012, 29 (5) , 893-903. https://doi.org/10.1080/073911012010525025
    17. Aditi Narendra Borkar, Manoj Kumar Rout, Ramakrishna V. Hosur, . Visualization of Early Events in Acetic Acid Denaturation of HIV-1 Protease: A Molecular Dynamics Study. PLoS ONE 2011, 6 (6) , e19830. https://doi.org/10.1371/journal.pone.0019830
    18. Massimiliano Bonomi, Alessandro Barducci, Francesco L. Gervasio, Michele Parrinello, . Multiple Routes and Milestones in the Folding of HIV–1 Protease Monomer. PLoS ONE 2010, 5 (10) , e13208. https://doi.org/10.1371/journal.pone.0013208
    19. Shawn Martin, Aidan Thompson, Evangelos A. Coutsias, Jean-Paul Watson. Topology of cyclo-octane energy landscape. The Journal of Chemical Physics 2010, 132 (23) https://doi.org/10.1063/1.3445267
    20. Alessandro Lentini, Claudio Tabolacci, Sonia Melino, Bruno Provenzano, Simone Beninati. Post-translational modification of glutamine and lysine residues of HIV-1 aspartyl protease by transglutaminase increases its catalytic activity. Biochemical and Biophysical Research Communications 2010, 393 (3) , 546-550. https://doi.org/10.1016/j.bbrc.2010.02.060
    21. Dariusz Ekonomiuk, Amedeo Caflisch. Activation of the West Nile virus NS3 protease: Molecular dynamics evidence for a conformational selection mechanism. Protein Science 2009, 18 (5) , 1003-1011. https://doi.org/10.1002/pro.110
    22. Mao‐Cai Yan, Yu Sha, Jian Wang, Xu‐Qiong Xiong, Jin‐Hong Ren, Mao‐Sheng Cheng. Molecular dynamics simulations of HIV‐1 protease monomer: Assembly of N‐terminus and C‐terminus into β‐sheet in water solution. Proteins: Structure, Function, and Bioinformatics 2008, 70 (3) , 731-738. https://doi.org/10.1002/prot.21539
    23. RA Broglia, Y Levy, G Tiana. HIV-1 protease folding and the design of drugs which do not create resistance. Current Opinion in Structural Biology 2008, 18 (1) , 60-66. https://doi.org/10.1016/j.sbi.2007.10.004
    24. Massimiliano Bonomi, Francesco L. Gervasio, Guido Tiana, Davide Provasi, Ricardo A. Broglia, Michele Parrinello. Insight into the Folding Inhibition of the HIV-1 Protease by a Small Peptide. Biophysical Journal 2007, 93 (8) , 2813-2821. https://doi.org/10.1529/biophysj.107.106369
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    26. Yaakov Levy, José N. Onuchic. Energy Landscapes of Protein Self-Assembly: Lessons from Native Topology-Based Models. 2007, 37-51. https://doi.org/10.1007/978-3-540-46375-7_4
    27. Manuela Cavallari, Caterina Ghio, Susanna Monti, Mauro Ferrario, Amos Maritan, Paolo Carloni. Partially folded states of HIV-1 protease: Molecular dynamics simulations and ligand binding. Journal of Molecular Structure: THEOCHEM 2006, 769 (1-3) , 111-121. https://doi.org/10.1016/j.theochem.2006.04.042
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    29. Y. Levy†, I. Last, J. Jortner. Dynamics of fission and Coulomb explosion of multicharged large finite systems. Molecular Physics 2006, 104 (8) , 1227-1237. https://doi.org/10.1080/00268970500525630
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