title: Compensatory role of double mutation N348I/M184V on nevirapine binding landscape: insight from molecular dynamics simulation.
abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTI) have emerged as gold standards in current anti-AIDS drug discovery and development by allosterically inhibiting HIV reverse transcriptase (HIV-RT). Connection sub-domain mutation, N348I and the M184V active site mutation decreases HIV-1 RT susceptibility to NNRTI, nevirapine (NVP), whereas concurrence of both mutations improves enzyme susceptibility to NVP. Molecular dynamics simulation and enhanced post-dynamics analyses were applied to gain molecular insight into occurrence of N348I, M184V and N348I/M184V double mutations and their effect on NVP binding landscape. Results showed that the presence of the double mutation (N348I/M184V) ameliorates the drastic effects of connection sub-domain mutation, N348I alone on NVP binding, which correlates with experimental findings. We showed that the binding of NVP to the NNRTI binding pocket (NNIBP) is drastically distorted in the presence of connection sub-domain mutation, N348I and may further explain the impaired motions of mutant RTs compared to the wild type. The residue based fluctuation further suggested that the occurrence of N348I decreased the overall flexibility of NVP-HIV-RT complex whereas concurrence of N348I/M184V double mutation restored the conformational flexibility as compared to single mutant. This phenomenon was further validated by the trends of binding free energy as well as the per-residue footprints which showed an increased ∆Gbind in case of N348I/M184V double mutant as compared to N348I variant. Further, for the first time residue interaction network highlighted the structural changes due to occurrence of M184V and N348I mutations which gives a conclusive evidence of these mutations. This work provides the most comprehensive analysis of NVP resistance and the impact of double (N348I/M184V) mutation to date from a dynamics perspective and provides information that should prove useful for understanding the drug resistance mechanism against NVP. The results also provide preliminary data which might prove useful for the design of novel inhibitors that are less susceptible to drug resistance.
authors.affiliation: School of Health Sciences, University of KwaZulu-Natal, Westville, Durban, 4001, South Africa.
authors.forename: Wilson
authors.initials: W
authors.lastname: Karubiu
authors.forename: Soumendranath
authors.initials: S
authors.lastname: Bhakat
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D001665:Binding Sites; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D019829:Nevirapine / Q000737:chemistry* / Q000378:metabolism*; D025341:Principal Component Analysis; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
references.citation: J Acquir Immune Defic Syndr. 2012 Oct 1;61(2):153-7
references.pmid: 22743599
references.citation: Antiviral Res. 2009 Jun;82(3):115-21
references.pmid: 19428602
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Comput Chem. 2004 Oct;25(13):1605-12
references.pmid: 15264254
references.citation: J Infect Dis. 2010 Apr 1;201(7):1054-62
references.pmid: 20170373
references.citation: Trends Biochem Sci. 2011 Apr;36(4):179-82
references.pmid: 21345680
references.citation: J Mol Biol. 1999 Jan 29;285(4):1711-33
references.pmid: 9917407
references.citation: Bioinformatics. 2011 Jun 1;27(11):1575-7
references.pmid: 21471012
references.citation: PLoS Med. 2007 Dec;4(12):e335
references.pmid: 18052601
references.citation: Antimicrob Agents Chemother. 2011 Apr;55(4):1806-9
references.pmid: 21282419
references.citation: Bioinformatics. 2011 Jul 15;27(14):2003-5
references.pmid: 21493660
references.citation: Acc Chem Res. 2000 Dec;33(12):889-97
references.pmid: 11123888
references.citation: Chem Rev. 2014 Jan 8;114(1):493-537
references.pmid: 24024775
references.citation: Antiviral Res. 2011 Nov;92(2):139-49
references.pmid: 21896288
references.citation: Curr Opin Struct Biol. 2004 Dec;14(6):716-30
references.pmid: 15582396
references.citation: J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):293-6
references.pmid: 22828721
references.citation: Antiviral Res. 2010 Jan;85(1):39-58
references.pmid: 19887088
references.citation: J Am Chem Soc. 2005 Dec 14;127(49):17253-60
references.pmid: 16332074
references.citation: Antimicrob Agents Chemother. 2010 Jan;54(1):72-7
references.pmid: 19901096
references.citation: J Chem Theory Comput. 2013 Jul 9;9(7):3084-95
references.pmid: 26583988
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: Clin Infect Dis. 2012 Sep;55(5):737-45
references.pmid: 22618567
references.citation: J Chem Theory Comput. 2012 May 8;8(5):1542-1555
references.pmid: 22582031
references.citation: Nat Struct Mol Biol. 2012 Jan 22;19(2):253-9
references.pmid: 22266819
references.citation: J Chem Inf Model. 2011 Jan 24;51(1):69-82
references.pmid: 21117705
references.citation: Biopolymers. 2000-2001;56(4):275-91
references.pmid: 11754341
references.citation: J Biol Chem. 2010 Dec 3;285(49):38700-9
references.pmid: 20876531
references.citation: J Virol. 2008 Apr;82(7):3261-70
references.pmid: 18216099
references.citation: J Virol. 2014 Feb;88(3):1536-47
references.pmid: 24227862
references.citation: J Virol. 2002 Oct;76(19):10015-9
references.pmid: 12208978
references.citation: Antimicrob Agents Chemother. 2010 Feb;54(2):728-33
references.pmid: 20008779
references.citation: Mol Biosyst. 2014 Aug;10(8):2215-28
references.pmid: 24931725
references.citation: Proteins. 2010 Jun;78(8):1950-8
references.pmid: 20408171
references.citation: AIDS Rev. 2008 Oct-Dec;10(4):224-35
references.pmid: 19092978
references.citation: Phys Chem Chem Phys. 2013 May 28;15(20):7731-9
references.pmid: 23595060