title: Residue-level resolution of alphavirus envelope protein interactions in pH-dependent fusion.
abstract: Alphavirus envelope proteins, organized as trimers of E2-E1 heterodimers on the surface of the pathogenic alphavirus, mediate the low pH-triggered fusion of viral and endosomal membranes in human cells. The lack of specific treatment for alphaviral infections motivates our exploration of potential antiviral approaches by inhibiting one or more fusion steps in the common endocytic viral entry pathway. In this work, we performed constant pH molecular dynamics based on an atomic model of the alphavirus envelope with icosahedral symmetry. We have identified pH-sensitive residues that cause the largest shifts in thermodynamic driving forces under neutral and acidic pH conditions for various fusion steps. A series of conserved interdomain His residues is identified to be responsible for the pH-dependent conformational changes in the fusion process, and ligand binding sites in their vicinity are anticipated to be potential drug targets aimed at inhibiting viral infections.
authors: Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, MI 48109; and.
authors: Xiancheng
authors: X
authors: Zeng
authors: Department of Biology, Indiana University, Bloomington, IN 47405-7000.
authors: Suchetana
authors: S
authors: Mukhopadhyay
authors: Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, MI 48109; and brookscl@umich.edu.
authors: Charles L
authors: CL
authors: Brooks
mesh_terms: D000524:Alphavirus / Q000378:metabolism*; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D008561:Membrane Fusion; D013816:Thermodynamics; D014759:Viral Envelope Proteins / Q000378:metabolism*
chemical_list: D014759:Viral Envelope Proteins
keywords: alphavirus; constant pH molecular dynamics; envelope protein; membrane fusion; pH
references: J Virol. 2013 Sep;87(18):10255-62
references: 23864626
references: J Virol. 2011 Dec;85(23):12271-9
references: 21937662
references: Virology. 2005 Feb 20;332(2):511-8
references: 15680416
references: Biophys J. 2005 Jul;89(1):141-57
references: 15863480
references: EMBO J. 2000 Oct 2;19(19):5081-91
references: 11013211
references: Viruses. 2010 Mar 26;2(4):796-825
references: 21546978
references: Cell. 2006 Feb 24;124(4):729-40
references: 16497584
references: Future Microbiol. 2009 Sep;4(7):837-56
references: 19722838
references: J Mol Biol. 2011 Dec 2;414(3):442-59
references: 22001018
references: J Cell Biol. 1992 Jan;116(2):339-48
references: 1370493
references: J Mol Biol. 1998;283(1):71-81
references: 9761674
references: Adv Protein Chem. 1970;24:1-95
references: 4912353
references: J Virol. 2006 Nov;80(22):11362-9
references: 16971447
references: J Virol. 2012 Dec;86(24):13609-20
references: 23035234
references: Structure. 2006 Jan;14(1):75-86
references: 16407067
references: Curr Opin Cell Biol. 2009 Aug;21(4):582-8
references: 19443190
references: J Virol. 2004 Dec;78(24):13543-52
references: 15564465
references: Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13362-7
references: 23898184
references: J Virol. 2003 Mar;77(5):2981-9
references: 12584323
references: J Comput Chem. 2009 Jul 30;30(10):1545-614
references: 19444816
references: J Cell Biol. 1996 Aug;134(4):863-72
references: 8769412
references: J Virol. 2009 May;83(9):4670-7
references: 19244325
references: Exp Cell Res. 1984 Jan;150(1):36-46
references: 6198190
references: Structure. 2006 Jan;14(1):63-73
references: 16407066
references: Cell. 1995 Feb 24;80(4):621-30
references: 7867069
references: J Virol. 1992 Dec;66(12):7309-18
references: 1433520
references: J Virol. 1998 Feb;72(2):1534-41
references: 9445057
references: Nature. 2010 Dec 2;468(7324):705-8
references: 21124457
references: Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10648-52
references: 7479858
references: Cell. 2001 Apr 6;105(1):137-48
references: 11301009
references: PLoS Pathog. 2007 Jun;3(6):e89
references: 17604450
references: Science. 2007 Dec 21;318(5858):1860-1
references: 18096785
references: J Virol. 2011 Sep;85(18):9327-33
references: 21752915
references: Curr Opin Virol. 2013 Apr;3(2):151-8
references: 23623639
references: Proteins. 2004 Sep 1;56(4):738-52
references: 15281127
references: Physiol Rev. 1981 Apr;61(2):296-434
references: 7012859
references: J Virol. 2001 Feb;75(4):2010-3
references: 11160702
references: Virol J. 2011;8:304
references: 21676248
references: EMBO J. 2002 Sep 2;21(17):4402-10
references: 12198142
references: J Virol. 1993 Dec;67(12):7597-607
references: 8230478
references: Nat Rev Microbiol. 2010 Jul;8(7):491-500
references: 20551973
references: Cell. 2001 Apr 6;105(1):127-36
references: 11301008
references: J Am Chem Soc. 2010 Jun 2;132(21):7258-9
references: 20446661
references: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6795-9
references: 23569243
references: J Virol. 2002 Jul;76(14):7239-46
references: 12072523
references: J Virol. 2000 Mar;74(6):2663-70
references: 10684281
references: J Virol. 2004 Apr;78(7):3312-8
references: 15016852
references: J Chem Theory Comput. 2011 Aug 9;7(8):2617-29
references: 26606635
references: Elife. 2013;2:e00435
references: 23577234
references: J Virol. 2002 Nov;76(22):11645-58
references: 12388725
references: Proteins. 2011 Dec;79(12):3276-86
references: 22002886
references: J Biol Chem. 2007 Mar 2;282(9):6752-62
references: 17192272
references: Proteins. 2014 Jul;82(7):1319-31
references: 24375620
references: J Virol. 2011 Jun;85(11):5644-50
references: 21430054
references: J Am Chem Soc. 2014 Feb 26;136(8):3097-107
references: 24495192
references: J Gen Virol. 2002 Jul;83(Pt 7):1535-45
references: 12075072
references: J Am Chem Soc. 2011 Dec 7;133(48):19393-8
references: 22026371
references: J Virol. 2001 Oct;75(19):9532-7
references: 11533216
references: J Virol. 2013 Apr;87(8):4352-9
references: 23388718
references: Adv Protein Chem. 1964;19:223-86
references: 14268785
references: Mol Cell. 2000 Feb;5(2):255-66
references: 10882067
references: Curr Top Microbiol Immunol. 2005;285:25-66
references: 15609500
references: Nature. 2010 Dec 2;468(7324):709-12
references: 21124458
references: J Biol Chem. 2003 Feb 28;278(9):7189-98
references: 12493775
references: Nature. 2004 Jan 22;427(6972):320-5
references: 14737160
references: Nat Struct Mol Biol. 2008 Jul;15(7):690-8
references: 18596815
references: J Phys Chem B. 2012 Aug 2;116(30):8805-11
references: 22694266
references: J Virol. 2013 Jul;87(13):7680-7
references: 23637415
references: EMBO J. 2011 Sep 14;30(18):3854-63
references: 21829169
references: J Virol. 2013 Apr;87(7):3774-81
references: 23325694
references: J Virol. 2009 Nov;83(21):11298-306
references: 19692469
references: Curr Top Microbiol Immunol. 2005;285:1-23
references: 15609499
references: Annu Rev Biochem. 2010;79:803-33
references: 20196649
references: Drug Discov Today. 2013 Oct;18(19-20):969-83
references: 23684571
references: Protein Sci. 2013 May;22(5):595-604
references: 23450521