Three Major Phosphoacceptor Sites in HIV-1 Capsid Protein Enhances its Structural Stability and Resistance Against the Inhibitor: Explication Through Molecular Dynamics Simulation, Molecular Docking and DFT Analysis

Author(s): Nouman Rasool*, Waqar Hussain.

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 1 , 2020

Become EABM
Become Reviewer

Abstract:

Background: Human Immunodeficiency Virus 1 (HIV-1) is a lentivirus, which causes various HIV-associated infections. The HIV-1 core dissociation is essential for viral cDNA synthesis and phosphorylation of HIV-1 capsid protein (HIV-1 CA) plays an important role in it.

Objective: The aim of this study was to explicate the role of three phosphoserine sites i.e. Ser109, Ser149 and Ser178 in the structural stability of HIV-1 CA, and it’s binding with GS-CA1, a novel potent inhibitor.

Methods: Eight complexes were analyzed and Molecular Dynamics (MD) simulations were performed to observe the stability of HIV-1 CA in the presence and absence of phosphorylation of serine residues at four different temperatures i.e. 300K, 325K, 340K and 350K, along with molecular docking and DFT analysis.

Results: The structures showed maximum stability in the presence of phosphorylated serine residue. However, GS-CA1 docked most strongly with the native structure of HIV-1 CA i.e. binding affinity was -8.5 kcal/mol (Ki = 0.579 µM).

Conclusion: These results suggest that the phosphorylation of these three serine residues weakens the binding of GS-CA1 with CA and casts derogatory effect on inhibition potential of this inhibitor, but it supports the stability of HIV-1 CA structure that can enhance regulation and replication of HIV-1 in host cells.

Keywords: HIV-1 Capsid, GS-CA1, phosphorylation, molecular dynamics simulation, molecular docking, DFT analysis.

[1]
Fauci, A.S. HIV and AIDS: 20 years of science. Nat. Med., 2003, 9(7), 839-843.
[http://dx.doi.org/10.1038/nm0703-839] [PMID: 12835701]
[2]
Liu, G.; Wang, W.; Wan, Y.; Ju, X.; Gu, S. Application of 3D-QSAR, pharmacophore, and molecular docking in the molecular design of diarylpyrimidine derivatives as HIV-1 nonnucleoside reverse transcriptase inhibitors. Int. J. Mol. Sci., 2018, 19(5), 1436.
[http://dx.doi.org/10.3390/ijms19051436] [PMID: 29751616]
[3]
Organization, W.H. Health literacy. The solid facts. Health, 2017.
[4]
Chen, X.; Zhan, P.; Li, D.; De Clercq, E.; Liu, X. Recent advances in DAPYs and related analogues as HIV-1 NNRTIs. Curr. Med. Chem., 2011, 18(3), 359-376.
[http://dx.doi.org/10.2174/092986711794839142] [PMID: 21143120]
[5]
Das, K.; Martinez, S.E.; Bauman, J.D.; Arnold, E. HIV-1 reverse transcriptase complex with DNA and nevirapine reveals non-nucleoside inhibition mechanism. Nat. Struct. Mol. Biol., 2012, 19(2), 253-259.
[http://dx.doi.org/10.1038/nsmb.2223] [PMID: 22266819]
[6]
Butt, A.H.; Rasool, N.; Khan, Y.D. Predicting membrane proteins and their types by extracting various sequence features into Chou’s general PseAAC. Mol. Biol. Rep., 2018, 45(6), 2295-2306.
[http://dx.doi.org/10.1007/s11033-018-4391-5] [PMID: 30238411]
[7]
Henderson, L.E.; Bowers, M.A.; Sowder, R.C., II; Serabyn, S.A.; Johnson, D.G.; Bess, J.W., Jr; Arthur, L.O.; Bryant, D.K.; Fenselau, C. Gag proteins of the highly replicative MN strain of human immunodeficiency virus type 1: posttranslational modifications, proteolytic processings, and complete amino acid sequences. J. Virol., 1992, 66(4), 1856-1865.
[PMID: 1548743]
[8]
Cartier, C.; Sivard, P.; Tranchat, C.; Decimo, D.; Desgranges, C.; Boyer, V. Identification of three major phosphorylation sites within HIV-1 capsid. Role of phosphorylation during the early steps of infection. J. Biol. Chem., 1999, 274(27), 19434-19440.
[http://dx.doi.org/10.1074/jbc.274.27.19434] [PMID: 10383459]
[9]
Goff, S.P. Host factors exploited by retroviruses. Nat. Rev. Microbiol., 2007, 5(4), 253-263.
[http://dx.doi.org/10.1038/nrmicro1541] [PMID: 17325726]
[10]
Freed, E.O. HIV-1 and the host cell: an intimate association. Trends Microbiol., 2004, 12(4), 170-177.
[http://dx.doi.org/10.1016/j.tim.2004.02.001] [PMID: 15051067]
[11]
Humphrey, S.J.; James, D.E.; Mann, M. Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol. Metab., 2015, 26(12), 676-687.
[http://dx.doi.org/10.1016/j.tem.2015.09.013] [PMID: 26498855]
[12]
Takeuchi, H.; Saito, H.; Noda, T.; Miyamoto, T.; Yoshinaga, T.; Terahara, K.; Ishii, H.; Tsunetsugu-Yokota, Y.; Yamaoka, S. Phosphorylation of the HIV-1 capsid by MELK triggers uncoating to promote viral cDNA synthesis. PLoS Pathog., 2017, 13(7)e1006441
[http://dx.doi.org/10.1371/journal.ppat.1006441] [PMID: 28683086]
[13]
Gres, A.T.; Kirby, K.A. KewalRamani, V.N.; Tanner, J.J.; Pornillos, O.; Sarafianos, S.G. X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability. Science, 2015, 349(6243), 99-103.
[http://dx.doi.org/10.1126/science.aaa5936] [PMID: 26044298]
[14]
Carnes, S.K.; Sheehan, J.H.; Aiken, C. Inhibitors of the HIV-1 capsid, a target of opportunity. Curr. Opin. HIV AIDS, 2018, 13(4), 359-365.
[http://dx.doi.org/10.1097/COH.0000000000000472] [PMID: 29782334]
[15]
Kelly, B.N.; Kyere, S.; Kinde, I.; Tang, C.; Howard, B.R.; Robinson, H.; Sundquist, W.I.; Summers, M.F.; Hill, C.P. Structure of the antiviral assembly inhibitor CAP-1 complex with the HIV-1 CA protein. J. Mol. Biol., 2007, 373(2), 355-366.
[http://dx.doi.org/10.1016/j.jmb.2007.07.070] [PMID: 17826792]
[16]
Rasaiyaah, J.; Tan, C.P.; Fletcher, A.J.; Price, A.J.; Blondeau, C.; Hilditch, L.; Jacques, D.A.; Selwood, D.L.; James, L.C.; Noursadeghi, M.; Towers, G.J. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature, 2013, 503(7476), 402-405.
[http://dx.doi.org/10.1038/nature12769] [PMID: 24196705]
[17]
Lamorte, L.; Titolo, S.; Lemke, C.T.; Goudreau, N.; Mercier, J-F.; Wardrop, E.; Shah, V.B.; von Schwedler, U.K.; Langelier, C.; Banik, S.S.; Aiken, C.; Sundquist, W.I.; Mason, S.W. Discovery of novel small-molecule HIV-1 replication inhibitors that stabilize capsid complexes. Antimicrob. Agents Chemother., 2013, 57(10), 4622-4631.
[http://dx.doi.org/10.1128/AAC.00985-13] [PMID: 23817385]
[18]
Zhang, H.; Zhao, Q.; Bhattacharya, S.; Waheed, A.A.; Tong, X.; Hong, A.; Heck, S.; Curreli, F.; Goger, M.; Cowburn, D.; Freed, E.O.; Debnath, A.K. A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J. Mol. Biol., 2008, 378(3), 565-580.
[http://dx.doi.org/10.1016/j.jmb.2008.02.066] [PMID: 18374356]
[19]
Chen, N-Y.; Zhou, L.; Gane, P.J.; Opp, S.; Ball, N.J.; Nicastro, G.; Zufferey, M.; Buffone, C.; Luban, J.; Selwood, D.; Diaz-Griffero, F.; Taylor, I.; Fassati, A. HIV-1 capsid is involved in post-nuclear entry steps. Retrovirology, 2016, 13(1), 28.
[http://dx.doi.org/10.1186/s12977-016-0262-0] [PMID: 27107820]
[20]
Wang, W.; Zhou, J.; Halambage, U.D.; Jurado, K.A.; Jamin, A.V.; Wang, Y.; Engelman, A.N.; Aiken, C. Inhibition of HIV-1 maturation via small-molecule targeting of the amino-terminal domain in the viral capsid protein. J. Virol., 2017, 91(9), e02155-e02116.
[http://dx.doi.org/10.1128/JVI.02155-16] [PMID: 28202766]
[21]
Thenin-Houssier, S.; de Vera, I.M.S.; Pedro-Rosa, L.; Brady, A.; Richard, A.; Konnick, B.; Opp, S.; Buffone, C.; Fuhrmann, J.; Kota, S.; Billack, B.; Pietka-Ottlik, M.; Tellinghuisen, T.; Choe, H.; Spicer, T.; Scampavia, L.; Diaz-Griffero, F.; Kojetin, D.J.; Valente, S.T. Ebselen, a small-Molecule capsid inhibitor of HIV-1 replication. Antimicrob. Agents Chemother., 2016, 60(4), 2195-2208.
[http://dx.doi.org/10.1128/AAC.02574-15] [PMID: 26810656]
[22]
Tse, W.; Link, J.; Mulato, M. 24th Conference on Retroviruses and Opportunistic Infections (CROI 2017), 2017.
[23]
Jarvis, L.M.; Conquering, H. IV’s capsid. Chem. Eng. News, 2017, 95(31), 23-25.
[http://dx.doi.org/10.1021/cen-v089n031.p023]
[24]
Perrier, M.; Bertine, M.; Le Hingrat, Q.; Joly, V.; Visseaux, B.; Collin, G.; Landman, R.; Yazdanpanah, Y.; Descamps, D.; Charpentier, C. Prevalence of gag mutations associated with in vitro resistance to capsid inhibitor GS-CA1 in HIV-1 antiretroviral-naive patients. J. Antimicrob. Chemother., 2017, 72(10), 2954-2955.
[http://dx.doi.org/10.1093/jac/dkx208] [PMID: 29091184]
[25]
Zuo, X.; Huo, Z.; Kang, D.; Wu, G.; Zhou, Z.; Liu, X.; Zhan, P. Current insights into anti-HIV drug discovery and development: a review of recent patent literature (2014-2017). Expert Opin. Ther. Pat., 2018, 28(4), 299-316.
[http://dx.doi.org/10.1080/13543776.2018.1438410] [PMID: 29411697]
[26]
Hunter, A.D. ACS Publications, 1997.
[27]
Humphrey, W.; Dalke, A.; Schulten, K. VMD: visual molecular dynamics. J. Mol. Graph., 1996, 14(1) 33-38, 27-28.
[http://dx.doi.org/10.1016/0263-7855(96)00018-5] [PMID: 8744570]
[28]
MacKerell, A.D., Jr; Bashford, D.; Bellott, M.; Dunbrack, R.L., Jr; Evanseck, J.D.; Field, M.J.; Fischer, S.; Gao, J.; Guo, H.; Ha, S.; Joseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F.T.; Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D.T.; Prodhom, B.; Reiher, W.E.; Roux, B.; Schlenkrich, M.; Smith, J.C.; Stote, R.; Straub, J.; Watanabe, M.; Wiórkiewicz-Kuczera, J.; Yin, D.; Karplus, M. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B, 1998, 102(18), 3586-3616.
[http://dx.doi.org/10.1021/jp973084f] [PMID: 24889800]
[29]
Homouz, D.; Joyce-Tan, K.H.; Shahir Shamsir, M.; Moustafa, I.M.; Idriss, H. Molecular dynamics simulations suggest changes in electrostatic interactions as a potential mechanism through which serine phosphorylation inhibits DNA Polymerase β’s activity. J. Mol. Graph. Model., 2018, 79, 192-193.
[PMID: 29223917]
[30]
Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1, 19-25.
[http://dx.doi.org/10.1016/j.softx.2015.06.001]
[31]
Saito, M. Molecular dynamics simulations of proteins in water without the truncation of long-range Coulomb interactions. Mol. Simul., 1992, 8(6), 321-333.
[http://dx.doi.org/10.1080/08927029208022487]
[32]
Cheatham, T.I.; Miller, J.; Fox, T.; Darden, T.; Kollman, P. Molecular dynamics simulations on solvated biomolecular systems: the particle mesh Ewald method leads to stable trajectories of DNA, RNA, and proteins. J. Am. Chem. Soc., 1995, 117(14), 4193-4194.
[http://dx.doi.org/10.1021/ja00119a045]
[33]
Hess, B.; Bekker, H.; Berendsen, H.J.; Fraaije, J.G. LINCS: a linear constraint solver for molecular simulations. J. Comput. Chem., 1997, 18(12), 1463-1472.
[http://dx.doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463:AID-JCC4>3.0.CO;2-H]
[34]
Turner, P. XMGRACE, Version 5.1. 19. Center for Coastal and Land-Margin Research; Oregon Graduate Institute of Science and Technology: Beaverton, OR, 2005.
[35]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[36]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[37]
Neese, F. The ORCA program system. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2012, 2(1), 73-78.
[http://dx.doi.org/10.1002/wcms.81]
[38]
Pikkemaat, M.G.; Linssen, A.B.; Berendsen, H.J.; Janssen, D.B. Molecular dynamics simulations as a tool for improving protein stability. Protein Eng., 2002, 15(3), 185-192.
[http://dx.doi.org/10.1093/protein/15.3.185] [PMID: 11932489]
[39]
Ai, C.; Li, Y.; Wang, Y.; Li, W.; Dong, P.; Ge, G.; Yang, L. Investigation of binding features: effects on the interaction between CYP2A6 and inhibitors. J. Comput. Chem., 2010, 31(9), 1822-1831.
[http://dx.doi.org/10.1002/jcc.21455] [PMID: 20336802]
[40]
Gogoi, D.; Baruah, V.J.; Chaliha, A.K.; Kakoti, B.B.; Sarma, D.; Buragohain, A.K. Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening. Comput. Biol. Chem., 2017, 69, 28-40.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.04.005] [PMID: 28552695]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 23
ISSUE: 1
Year: 2020
Page: [41 - 54]
Pages: 14
DOI: 10.2174/1386207323666191213142223
Price: $65

Article Metrics

PDF: 12