title: Comparative molecular dynamics simulation of Hepatitis C Virus NS3/4A protease (Genotypes 1b, 3a and 4b) predicts conformational instability of the catalytic triad in drug resistant strains.
abstract: The protease domain of the Hepatitis C Virus (HCV) nonstructural protein 3 (NS3) has been targeted for inhibition by several direct-acting antiviral drugs. This approach has had marked success to treat infections caused by HCV genotype 1 predominant in the USA, Europe, and Japan. However, genotypes 3 and 4, dominant in developing countries, are resistant to a number of these drugs and little progress has been made towards understanding the structural basis of their drug resistivity. We have previously developed a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active sites of the NS3 proteases of HCV-1b and 4a in relation to their catalytic activity and drug susceptibility. Here, we improved the methodology, extended the analysis to include genotype 3a (predominant in South Asia including Pakistan), and compared the results of the three genotypes (1b, 3a and 4a). The 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) indicate conformational instability of the catalytic site in HCV-3a and 4a compared to that of HCV-1b NS3 protease. The divergence is gradual and genotype-dependent, with HCV-1b being the most stable, HCV-4a being the most unstable and HCV-3a representing an intermediate state. These results suggest that the structural dynamics behavior, more than the rigid structure, could be related to the altered catalytic activity and drug susceptibility seen in NS3 proteases of HCV-3a and 4a.
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Halleran
authors.affiliation: Drug Discovery and Structural Biology group, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Moazur
authors.initials: M
authors.lastname: Rahman
authors.affiliation: Drug Discovery and Structural Biology group, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Mazhar
authors.initials: M
authors.lastname: Iqbal
authors.forename: Muhammad Ikram
authors.initials: MI
authors.lastname: Anwar
authors.affiliation: Drug Discovery and Structural Biology group, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad, Pakistan.
authors.forename: Muhmad Ikram
authors.initials: MI
authors.lastname: Anwar
authors.affiliation: Department of Zoology, Faculty of Science, Cairo University, Giza, Egypt.
authors.forename: Salwa
authors.initials: S
authors.lastname: Sabet
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Ackad
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Yousef
authors.affiliation: Department of Physics, College of Arts and Sciences, Southern Illinois University Edwardsville, Edwardsville, Illinois, United States of America; Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Yousef
mesh_terms: D000595:Amino Acid Sequence; D055162:Biocatalysis; D020134:Catalytic Domain; D024882:Drug Resistance, Viral / Q000235:genetics; D004795:Enzyme Stability; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir
references.citation: Virol J. 2010 Aug 26;7:203
references.pmid: 20796270
references.citation: Protein Expr Purif. 1999 Aug;16(3):440-7
references.pmid: 10425166
references.citation: J Infect Dis. 2013 Dec 1;208(11):1888-97
references.pmid: 23908491
references.citation: Gut Liver. 2011 Dec;5(4):406-17
references.pmid: 22195237
references.citation: Antimicrob Agents Chemother. 2012 Oct;56(10):5365-73
references.pmid: 22869572
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D387-92
references.pmid: 18931379
references.citation: Bioinformatics. 2006 Jan 15;22(2):195-201
references.pmid: 16301204
references.citation: J Biol Chem. 2010 Jul 23;285(30):22725-31
references.pmid: 20457607
references.citation: Proc Natl Acad Sci U S A. 1974 May;71(5):1643-7
references.pmid: 4525454
references.citation: J Mol Biol. 2001 Feb 2;305(5):1099-110
references.pmid: 11162117
references.citation: J Med Virol. 2001 Dec;65(4):671-80
references.pmid: 11745930
references.citation: Trends Microbiol. 2013 Dec;21(12):625-33
references.pmid: 24238778
references.citation: Nature. 1996 May 23;381(6580):272
references.pmid: 8692262
references.citation: PLoS One. 2012;7(12):e52467
references.pmid: 23285053
references.citation: J Med Virol. 2012 Nov;84(11):1744-50
references.pmid: 22997077
references.citation: Acta Crystallogr D Biol Crystallogr. 2011 Apr;67(Pt 4):235-42
references.pmid: 21460441
references.citation: Gastroenterology. 2011 Sep;141(3):1067-79
references.pmid: 21699793
references.citation: Chem Rev. 2002 Dec;102(12):4501-24
references.pmid: 12475199
references.citation: Antiviral Res. 2014 Mar;103:60-70
references.pmid: 24462696
references.citation: J Chem Inf Model. 2014 Feb 24;54(2):621-33
references.pmid: 23745769
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14757-62
references.pmid: 20696911
references.citation: Biophys J. 2010 Dec 1;99(11):3811-20
references.pmid: 21112306
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: Electrophoresis. 1997 Dec;18(15):2714-23
references.pmid: 9504803
references.citation: Viruses. 2010 Aug;2(8):1752-65
references.pmid: 21994705
references.citation: Hepatology. 2011 Apr;53(4):1090-9
references.pmid: 21480315
references.citation: Protein Sci. 1998 Apr;7(4):837-47
references.pmid: 9568891
references.citation: Antiviral Res. 2012 Jan;93(1):126-37
references.pmid: 22127068
references.citation: J Hepatol. 2011 Jun;54(6):1250-62
references.pmid: 21316497
references.citation: Biochim Biophys Acta. 2012 Oct;1820(10):1526-34
references.pmid: 22698669
references.citation: J Infect Dis. 2014 Mar 1;209(5):668-75
references.pmid: 24154738
references.citation: J Mol Biol. 1963 Jul;7:95-9
references.pmid: 13990617
references.citation: J Mol Biol. 1999 Jun 4;289(2):371-84
references.pmid: 10366511
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: Proteins. 2001 Nov 15;45(3):241-61
references.pmid: 11599028
references.citation: N Engl J Med. 2013 May 16;368(20):1878-87
references.pmid: 23607594
references.citation: Nature. 1992 Mar 5;356(6364):83-5
references.pmid: 1538787
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: J Mol Biol. 1996 Nov 22;264(1):121-36
references.pmid: 8950272
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3381-5
references.pmid: 12824332
references.citation: J Chem Theory Comput. 2013 Dec 10;9(12):5693-5705
references.pmid: 24587770
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Jul;59(Pt 7):1131-7
references.pmid: 12832755
references.citation: Clin Liver Dis. 2005 Aug;9(3):411-26, vi
references.pmid: 16023974
references.citation: PLoS One. 2012;7(7):e39652
references.pmid: 22792183
references.citation: J Biol Chem. 2000 Mar 10;275(10):7152-7
references.pmid: 10702283
references.citation: Virus Res. 2008 Feb;131(2):260-70
references.pmid: 18037183
references.citation: J Chem Inf Model. 2014 Apr 28;54(4):1208-17
references.pmid: 24689657
references.citation: J Biomol Struct Dyn. 2014;32(6):950-8
references.pmid: 23768174
references.citation: Virol J. 2011 Feb 08;8:55
references.pmid: 21303499
references.citation: Hepatology. 2013 Dec;58(6):1918-29
references.pmid: 23907700
references.citation: J Mol Biol. 1973 Feb 25;74(2):137-49
references.pmid: 4689953
references.citation: Liver Int. 2009 Jan;29 Suppl 1:74-81
references.pmid: 19207969
references.citation: Clin Infect Dis. 2014 Apr;58(7):928-36
references.pmid: 24399087
references.citation: Virol J. 2013 Dec 05;10:351
references.pmid: 24308812
references.citation: World J Gastroenterol. 2002 Dec;8(6):1088-93
references.pmid: 12439931
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 7;107(49):20986-91
references.pmid: 21084633
references.citation: Chem Rev. 2002 Dec;102(12):4609-26
references.pmid: 12475203
references.citation: Protein Sci. 1993 Sep;2(9):1511-9
references.pmid: 8401235
references.citation: PLoS One. 2014 Jan 21;9(1):e86413
references.pmid: 24466079