Conformational variation of an extreme drug resistant mutant of HIV protease

Shen, Chen-Hsiang; Chang, Yu-Chung; Agniswamy, Johnson; Harrison, Robert W.; Weber, Irene T.

doi:10.1016/j.jmgm.2015.09.006

Title: Conformational variation of an extreme drug resistant mutant of HIV protease

Journal Article · Tue Sep 08 00:00:00 EDT 2015 · Journal of Molecular Graphics and Modelling

DOI:https://doi.org/10.1016/j.jmgm.2015.09.006· OSTI ID:1222023

Shen, Chen-Hsiang ^[1]; Chang, Yu-Chung ^[1]; Agniswamy, Johnson ^[1]; Harrison, Robert W. ^[1]; Weber, Irene T. ^[1]

Georgia State Univ., Atlanta, GA (United States)

Molecular mechanisms leading to high level drug resistance have been analyzed for the clinical variant of HIV-1 protease bearing 20 mutations (PR20); which has several orders of magnitude worse affinity for tested drugs. Two crystal structures of ligand-free PR20 with the D25N mutation of the catalytic aspartate (PR20D25N) revealed three dimers with different flap conformations. The diverse conformations of PR20D25N included a dimer with one flap in a unique “tucked” conformation; directed into the active site. Analysis of molecular dynamics (MD) simulations of the ligand-free PR20 and wild-type enzymes showed that the mutations in PR20 alter the correlated interactions between two monomers in the dimer. The two flaps tend to fluctuate more independently in PR20 than in the wild type enzyme. Combining the results of structural analysis by X-ray crystallography and MD simulations; unusual flap conformations and weakly correlated inter-subunit motions may lead to the high level resistance of PR20.

View Accepted Manuscript (DOE)

View Accepted Manuscript (Publisher)

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31-109-Eng-38

OSTI ID:: 1222023

Alternate ID(s):: OSTI ID: 1250921

Journal Information:: Journal of Molecular Graphics and Modelling, Vol. 62, Issue C; ISSN 1093-3263

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

Citation Metrics:

Cited by: 21 works

Citation information provided by
Web of Science

References (54)

Retroviral proteases and their roles in virion maturation Konvalinka, Jan; Kräusslich, Hans-Georg; Müller, Barbara Virology, Vol. 479-480 https://doi.org/10.1016/j.virol.2015.03.021	journal	May 2015
Structure-based design of AIDS drugs and the development of resistance Wlodawer, Alexander Vox Sanguinis, Vol. 83 https://doi.org/10.1111/j.1423-0410.2002.tb05261.x	journal	August 2002
Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV Ghosh, Arun K.; Anderson, David D.; Weber, Irene T. Angewandte Chemie International Edition, Vol. 51, Issue 8 https://doi.org/10.1002/anie.201102762	journal	January 2012
Structure Based Drug Design for HIV Protease: From Molecular Modeling to Cheminformatics Volarath, Patra; Harrison, Robert; Weber, Irene Current Topics in Medicinal Chemistry, Vol. 7, Issue 10 https://doi.org/10.2174/156802607780906744	journal	May 2007
Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations Acevedo, Orlando; Ambrose, Zandrea; T. Flaherty, Patrick Current Pharmaceutical Design, Vol. 18, Issue 9 https://doi.org/10.2174/138161212799436421	journal	March 2012
Targeting structural flexibility in HIV-1 protease inhibitor binding Hornak, Viktor; Simmerling, Carlos Drug Discovery Today, Vol. 12, Issue 3-4 https://doi.org/10.1016/j.drudis.2006.12.011	journal	February 2007
Protease inhibitors effectively block cell-to-cell spread of HIV-1 between T cells Titanji, Boghuma; Aasa-Chapman, Marlen; Pillay, Deenan Retrovirology, Vol. 10, Issue 1 https://doi.org/10.1186/1742-4690-10-161	journal	January 2013
Basic concepts in RNA virus evolution. Domingo, E.; Escarmís, C.; Sevilla, N. The FASEB Journal, Vol. 10, Issue 8, p. 859-864 https://doi.org/10.1096/fasebj.10.8.8666162	journal	June 1996
Predictors of HIV Drug‐Resistance Mutations in a Large Antiretroviral‐Naive Cohort Initiating Triple Antiretroviral Therapy Harrigan, P. Richard; Hogg, Robert S.; Dong, Winnie W. Y. The Journal of Infectious Diseases, Vol. 191, Issue 3 https://doi.org/10.1086/427192	journal	February 2005
Higher Rates of Viral Suppression with Nonnucleoside Reverse Transcriptase Inhibitors Compared to Single Protease Inhibitors Are Not Explained by Better Adherence Weiser, Sheri D.; Guzman, David; Riley, Elise D. HIV Clinical Trials, Vol. 5, Issue 5 https://doi.org/10.1310/LNHD-K1R7-HQP5-HJCQ	journal	October 2004
Highly resistant HIV-1 proteases and strategies for their inhibition Weber, Irene T.; Kneller, Daniel W.; Wong-Sam, Andres Future Medicinal Chemistry, Vol. 7, Issue 8 https://doi.org/10.4155/fmc.15.44	journal	June 2015
Binding Kinetics of Darunavir to Human Immunodeficiency Virus Type 1 Protease Explain the Potent Antiviral Activity and High Genetic Barrier Dierynck, Inge; De Wit, Mieke; Gustin, Emmanuel Journal of Virology, Vol. 81, Issue 24 https://doi.org/10.1128/JVI.01184-07	journal	October 2007
Inhibition of autoprocessing of natural variants and multidrug resistant mutant precursors of HIV-1 protease by clinical inhibitors Louis, J. M.; Aniana, A.; Weber, I. T. Proceedings of the National Academy of Sciences, Vol. 108, Issue 22 https://doi.org/10.1073/pnas.1102278108	journal	May 2011
Enhanced Stability of Monomer Fold Correlates with Extreme Drug Resistance of HIV-1 Protease Louis, John M.; Tözsér, József; Roche, Julien Biochemistry, Vol. 52, Issue 43 https://doi.org/10.1021/bi400962r	journal	October 2013
HIV-1 Protease with 20 Mutations Exhibits Extreme Resistance to Clinical Inhibitors through Coordinated Structural Rearrangements Agniswamy, Johnson; Shen, Chen-Hsiang; Aniana, Annie Biochemistry, Vol. 51, Issue 13 https://doi.org/10.1021/bi2018317	journal	March 2012
Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20 Agniswamy, Johnson; Louis, John M.; Shen, Chen-Hsiang Journal of Medicinal Chemistry, Vol. 58, Issue 12 https://doi.org/10.1021/acs.jmedchem.5b00474	journal	March 2015
Design of gem -Difluoro- bis -Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation Ghosh, Arun K.; Yashchuk, Sofiya; Mizuno, Akira ChemMedChem, Vol. 10, Issue 1 https://doi.org/10.1002/cmdc.201402358	journal	October 2014
Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes Robbins, Arthur H.; Coman, Roxana M.; Bracho-Sanchez, Edith Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 3 https://doi.org/10.1107/S0907444909054298	journal	February 2010
Exploring the drug resistance of V32I and M46L mutant HIV-1 protease to inhibitor TMC114: Flap dynamics and binding mechanism Meher, Biswa Ranjan; Wang, Yixuan Journal of Molecular Graphics and Modelling, Vol. 56 https://doi.org/10.1016/j.jmgm.2014.11.003	journal	March 2015
“Wide-Open” 1.3 Å Structure of a Multidrug-Resistant HIV-1 Protease as a Drug Target Martin, Philip; Vickrey, John F.; Proteasa, Gheorghe Structure, Vol. 13, Issue 12 https://doi.org/10.1016/j.str.2005.11.005	journal	December 2005
Effect of the Active Site D25N Mutation on the Structure, Stability, and Ligand Binding of the Mature HIV-1 Protease Sayer, Jane M.; Liu, Fengling; Ishima, Rieko Journal of Biological Chemistry, Vol. 283, Issue 19 https://doi.org/10.1074/jbc.M708506200	journal	May 2008
Molecular dynamics simulations of HIV-1 protease with peptide substrate Harrison, Robert W.; Weber, Irene T. "Protein Engineering, Design and Selection", Vol. 7, Issue 11 https://doi.org/10.1093/protein/7.11.1353	journal	January 1994
Stiffness and energy conservation in molecular dynamics: An improved integrator Harrison, Robert W. Journal of Computational Chemistry, Vol. 14, Issue 9 https://doi.org/10.1002/jcc.540140912	journal	September 1993
Cross-docking study on InhA inhibitors: a combination of Autodock Vina and PM6-DH2 simulations to retrieve bio-active conformations Stigliani, Jean-Luc; Bernardes-Génisson, Vania; Bernadou, Jean Organic & Biomolecular Chemistry, Vol. 10, Issue 31 https://doi.org/10.1039/c2ob25602a	journal	January 2012
Improved Parameters for Generating Partial Charges: Correlation with Observed Dipole Moments Bagossi, Péter; Zahuczky, Gábor; Tözsér, József Journal of Molecular Modeling, Vol. 5, Issue 9 https://doi.org/10.1007/s008940050114	journal	September 1999
Molecular mechanics calculations on HIV-1 protease with peptide substrates correlate with experimental data Weber, Irene T.; Harrison, Robert W. "Protein Engineering, Design and Selection", Vol. 9, Issue 8 https://doi.org/10.1093/protein/9.8.679	journal	January 1996
Molecular mechanics analysis of drug-resistant mutants of HIV protease Weber, Irene T.; Harrison, Robert W. Protein Engineering, Design and Selection, Vol. 12, Issue 6 https://doi.org/10.1093/protein/12.6.469	journal	June 1999
Molecular dynamics simulations of 14 HIV protease mutants in complexes with indinavir Chen, Xianfeng; Weber, Irene T.; Harrison, Robert W. Journal of Molecular Modeling, Vol. 10, Issue 5-6 https://doi.org/10.1007/s00894-004-0205-x	journal	September 2004
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Macromolecular TLS Refinement in REFMAC at Moderate Resolutions Winn, Martyn D.; Murshudov, Garib N.; Papiz, Miroslav Z. Methods in Enzymology https://doi.org/10.1016/S0076-6879(03)74014-2	book	January 2003
Refinement of Macromolecular Structures by the Maximum-Likelihood Method Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3 https://doi.org/10.1107/S0907444996012255	journal	May 1997
Version 1.2 of the Crystallography and NMR system Brunger, Axel T. Nature Protocols, Vol. 2, Issue 11 https://doi.org/10.1038/nprot.2007.406	journal	October 2007
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions Krissinel, E.; Henrick, K. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12 https://doi.org/10.1107/S0907444904026460	journal	November 2004
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains Tie, Yunfeng; Boross, Peter I.; Wang, Yuan-Fang Journal of Molecular Biology, Vol. 338, Issue 2 https://doi.org/10.1016/j.jmb.2004.02.052	journal	April 2004
Caspase-3 binds diverse P4 residues in peptides as revealed by crystallography and structural modeling Fang, Bin; Fu, Guoxing; Agniswamy, Johnson Apoptosis, Vol. 14, Issue 5 https://doi.org/10.1007/s10495-009-0333-y	journal	May 2009
Insights into the functional role of protonation states in the HIV-1 protease-BEA369 complex: molecular dynamics simulations and free energy calculations Chen, Jianzhong; Yang, Maoyou; Hu, Guodong Journal of Molecular Modeling, Vol. 15, Issue 10 https://doi.org/10.1007/s00894-009-0452-y	journal	March 2009
Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters: HIV protease mutants altering hydrophobic clusters Shen, Chen-Hsiang; Wang, Yuan-Fang; Kovalevsky, Andrey Y. FEBS Journal, Vol. 277, Issue 18 https://doi.org/10.1111/j.1742-4658.2010.07771.x	journal	August 2010
Energetic basis for drug resistance of HIV-1 protease mutants against amprenavir Kar, Parimal; Knecht, Volker Journal of Computer-Aided Molecular Design, Vol. 26, Issue 2 https://doi.org/10.1007/s10822-012-9550-5	journal	February 2012
Domain communication in the dynamical structure of human immunodeficiency virus 1 protease. Harte, W. E.; Swaminathan, S.; Mansuri, M. M. Proceedings of the National Academy of Sciences, Vol. 87, Issue 22 https://doi.org/10.1073/pnas.87.22.8864	journal	November 1990
How does a symmetric dimer recognize an asymmetric substrate? a substrate complex of HIV-1 protease Prabu-Jeyabalan, Moses; Nalivaika, Ellen; Schiffer, Celia A. Journal of Molecular Biology, Vol. 301, Issue 5 https://doi.org/10.1006/jmbi.2000.4018	journal	September 2000
Conformational flexibility in the flap domains of ligand-free HIV protease Heaslet, Holly; Rosenfeld, Robin; Giffin, Mike Acta Crystallographica Section D Biological Crystallography, Vol. 63, Issue 8 https://doi.org/10.1107/S0907444907029125	journal	July 2007
HIV-1 protease molecular dynamics of a wild-type and of the V82F/I84V mutant: Possible contributions to drug resistance and a potential new target site for drugs Perryman, Alexander L.; Lin, Jung-Hsin; McCammon, J. Andrew Protein Science, Vol. 13, Issue 4 https://doi.org/10.1110/ps.03468904	journal	April 2004
Efficiency of a second-generation HIV-1 protease inhibitor studied by molecular dynamics and absolute binding free energy calculations Lepšík, M.; Kříž, Z.; Havlas, Z. Proteins: Structure, Function, and Bioinformatics, Vol. 57, Issue 2 https://doi.org/10.1002/prot.20192	journal	June 2004
Bio3d: an R package for the comparative analysis of protein structures Grant, B. J.; Rodrigues, A. P. C.; ElSawy, K. M. Bioinformatics, Vol. 22, Issue 21 https://doi.org/10.1093/bioinformatics/btl461	journal	August 2006
Molecular dynamics and protein function Karplus, M.; Kuriyan, J. Proceedings of the National Academy of Sciences, Vol. 102, Issue 19 https://doi.org/10.1073/pnas.0408930102	journal	May 2005
Protein Flexibility and Enzymatic Catalysis Kokkinidis, M.; Glykos, N. M.; Fadouloglou, V. E. Structural and Mechanistic Enzymology - Bringing Together Experiments and Computing https://doi.org/10.1016/B978-0-12-398312-1.00007-X	book	May 2012
HIV-1 Protease Substrate Binding and Product Release Pathways Explored with Coarse-Grained Molecular Dynamics Trylska, Joanna; Tozzini, Valentina; Chang, Chia-en A. Biophysical Journal, Vol. 92, Issue 12 https://doi.org/10.1529/biophysj.106.100560	journal	June 2007
Role of Conformational Fluctuations in the Enzymatic Reaction of HIV-1 Protease Piana, Stefano; Carloni, Paolo; Parrinello, Michele Journal of Molecular Biology, Vol. 319, Issue 2 https://doi.org/10.1016/S0022-2836(02)00301-7	journal	May 2002
Cooperative fluctuations of unliganded and substrate-bound HIV-1 protease: A structure-based analysis on a variety of conformations from crystallography and molecular dynamics simulations Kurt, Nese; Scott, Walter R. P.; Schiffer, Celia A. Proteins: Structure, Function, and Genetics, Vol. 51, Issue 3 https://doi.org/10.1002/prot.10350	journal	May 2003
Structures of Darunavir-Resistant HIV-1 Protease Mutant Reveal Atypical Binding of Darunavir to Wide Open Flaps Zhang, Ying; Chang, Yu-Chung E.; Louis, John M. ACS Chemical Biology, Vol. 9, Issue 6 https://doi.org/10.1021/cb4008875	journal	April 2014
Ligand modifications to reduce the relative resistance of multi-drug resistant HIV-1 protease Dewdney, Tamaria G.; Wang, Yong; Liu, Zhigang Bioorganic & Medicinal Chemistry, Vol. 21, Issue 23 https://doi.org/10.1016/j.bmc.2013.09.045	journal	December 2013
Global Dynamics of Proteins: Bridging Between Structure and Function Bahar, Ivet; Lezon, Timothy R.; Yang, Lee-Wei Annual Review of Biophysics, Vol. 39, Issue 1 https://doi.org/10.1146/annurev.biophys.093008.131258	journal	April 2010
Correlated motions are a fundamental property of β-sheets Fenwick, R. Bryn; Orellana, Laura; Esteban-Martín, Santi Nature Communications, Vol. 5, Issue 1 https://doi.org/10.1038/ncomms5070	journal	June 2014

Cited By (5)

Structural analyses of 2015-updated drug-resistant mutations in HIV-1 protease: an implication of protease inhibitor cross-resistance Su, Chinh Tran-To; Ling, Wei-Li; Lua, Wai-Heng BMC Bioinformatics, Vol. 17, Issue S19 https://doi.org/10.1186/s12859-016-1372-3	journal	December 2016
Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs Su, Chinh Tran-To; Koh, Darius Wen-Shuo; Gan, Samuel Ken-En Molecules, Vol. 24, Issue 18 https://doi.org/10.3390/molecules24183243	journal	September 2019
Highly drug‐resistant HIV‐1 protease reveals decreased intra‐subunit interactions due to clusters of mutations Kneller, Daniel W.; Agniswamy, Johnson; Harrison, Robert W. The FEBS Journal, Vol. 287, Issue 15 https://doi.org/10.1111/febs.15207	journal	January 2020
Flap Dynamics in Aspartic Proteases: A Computational Perspective Mahanti, Mukul; Bhakat, Soumendranath; Nilsson, Ulf J. Chemical Biology & Drug Design, Vol. 88, Issue 2 https://doi.org/10.1111/cbdd.12745	journal	March 2016
Evolution under Drug Pressure Remodels the Folding Free-Energy Landscape of Mature HIV-1 Protease Louis, John M.; Roche, Julien Journal of Molecular Biology, Vol. 428, Issue 13 https://doi.org/10.1016/j.jmb.2016.05.005	journal	July 2016

Similar Records

Structural Studies of a Rationally Selected Multi-Drug Resistant HIV-1 Protease Reveal Synergistic Effect of Distal Mutations on Flap Dynamics

Journal Article · Fri Dec 16 00:00:00 EST 2016 · PLoS ONE · OSTI ID:1222023

Agniswamy, Johnson; Louis, John M.; Roche, Julien; +3 more

Revertant mutation V48G alters conformational dynamics of highly drug resistant HIV protease PRS17

Journal Article · Wed Aug 11 00:00:00 EDT 2021 · Journal of Molecular Graphics and Modelling · OSTI ID:1222023

Burnaman, Shelley H.; Kneller, Daniel W.; Wang, Yuan-Fang; +2 more

Potent antiviral HIV-1 protease inhibitor combats highly drug resistant mutant PR20

Journal Article · Thu Aug 29 00:00:00 EDT 2019 · Biochemical and Biophysical Research Communications · OSTI ID:1222023

Kneller, Daniel W.; Agniswamy, Johnson; Ghosh, Arun K.; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Conformational variation of an extreme drug resistant mutant of HIV protease

Citation Formats

References (54)

Cited By (5)

Similar Records

Related Subjects