title: Structural and dynamical insights on HLA-DR2 complexes that confer susceptibility to multiple sclerosis in Sardinia: a molecular dynamics simulation study.
abstract: Sardinia is a major Island in the Mediterranean with a high incidence of multiple sclerosis, a chronic autoimmune inflammatory disease of the central nervous system. Disease susceptibility in Sardinian population has been associated with five alleles of major histocompatibility complex (MHC) class II DRB1 gene. We performed 120 ns of molecular dynamics simulation on one predisposing and one protective alleles, unbound and in complex with the two relevant peptides: Myelin Basic Protein and Epstein Barr Virus derived peptide. In particular we focused on the MHC peptide binding groove dynamics. The predisposing allele was found to form a stable complex with both the peptides, while the protective allele displayed stability only when bound with myelin peptide. The local flexibility of the MHC was probed dividing the binding groove into four compartments covering the well known peptide anchoring pockets. The predisposing allele in the first half cleft exhibits a narrower and more rigid groove conformation in the presence of myelin peptide. The protective allele shows a similar behavior, while in the second half cleft it displays a narrower and more flexible groove conformation in the presence of viral peptide. We further characterized these dynamical differences by evaluating H-bonds, hydrophobic and stacking interaction networks, finding striking similarities with super-type patterns emerging in other autoimmune diseases. The protective allele shows a defined preferential binding to myelin peptide, as confirmed by binding free energy calculations. All together, we believe the presented molecular analysis could help to design experimental assays, supports the molecular mimicry hypothesis and suggests that propensity to multiple sclerosis in Sardinia could be partly linked to distinct peptide-MHC interaction and binding characteristics of the antigen presentation mechanism.
authors.affiliation: Multiple Sclerosis Center, Department of Public Health and Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy. amit369@gmail.com
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.forename: Eleonora
authors.initials: E
authors.lastname: Cocco
authors.forename: Luigi
authors.initials: L
authors.lastname: Atzori
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Marrosu
authors.forename: Enrico
authors.initials: E
authors.lastname: Pieroni
mesh_terms: D000483:Alleles; D020022:Genetic Predisposition to Disease; D015802:HLA-DR2 Antigen / Q000737:chemistry* / Q000235:genetics*; D004854:Herpesvirus 4, Human; D006801:Humans; D007558:Italy; D056004:Molecular Dynamics Simulation; D009103:Multiple Sclerosis / Q000208:ethnology / Q000235:genetics*; D004676:Myelin Basic Protein / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D015802:HLA-DR2 Antigen; D004676:Myelin Basic Protein; D010446:Peptide Fragments
references.citation: Nature. 2011 Aug 10;476(7359):214-9
references.pmid: 21833088
references.citation: Annu Rev Immunol. 2005;23:683-747
references.pmid: 15771584
references.citation: Mol Immunol. 2011 Sep;48(15-16):1735-43
references.pmid: 21676462
references.citation: PLoS Comput Biol. 2012;8(3):e1002404
references.pmid: 22412359
references.citation: Eur Biophys J. 2011 Dec;40(12):1339-55
references.pmid: 22089251
references.citation: BMC Bioinformatics. 2007 Jul 04;8:238
references.pmid: 17608956
references.citation: Tissue Antigens. 2007 Jul;70(1):42-52
references.pmid: 17559580
references.citation: J Immunol. 1998 Apr 1;160(7):3363-73
references.pmid: 9531296
references.citation: Mol Immunol. 2010 Jan;47(4):649-57
references.pmid: 19910050
references.citation: J Med Chem. 1999 Nov 4;42(22):4650-8
references.pmid: 10579827
references.citation: Nat Rev Genet. 2008 Jul;9(7):516-26
references.pmid: 18542080
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W549-55
references.pmid: 17478500
references.citation: PLoS One. 2008 Mar 19;3(3):e1814
references.pmid: 18350151
references.citation: Immunity. 2009 Mar 20;30(3):348-57
references.pmid: 19303388
references.citation: Hum Mol Genet. 2001 Apr 1;10(8):881-9
references.pmid: 11285254
references.citation: PLoS One. 2008 Jun 11;3(6):e2403
references.pmid: 18545669
references.citation: J Comput Chem. 2006 Nov 15;27(14):1765-8
references.pmid: 16917862
references.citation: PLoS Comput Biol. 2008 Apr 04;4(4):e1000048
references.pmid: 18389056
references.citation: Mol Immunol. 2006 Feb;43(4):346-56
references.pmid: 16310048
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22219-24
references.pmid: 21115828
references.citation: Semin Immunol. 2011 Apr;23(2):84-91
references.pmid: 21306912
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: Hum Mol Genet. 2006 Sep 15;15(18):2813-24
references.pmid: 16905561
references.citation: Immunogenetics. 2005 Jun;57(5):304-14
references.pmid: 15868141
references.citation: PLoS One. 2012;7(4):e33972
references.pmid: 22509268
references.citation: J Mol Biol. 2008 Jun 13;379(4):787-802
references.pmid: 18479705
references.citation: FEBS Lett. 2011 Dec 1;585(23):3724-9
references.pmid: 21486562
references.citation: J Mol Biol. 1993 Dec 5;234(3):779-815
references.pmid: 8254673
references.citation: Biopolymers. 2009 Jan;91(1):14-27
references.pmid: 18767126
references.citation: Nature. 1993 Jul 1;364(6432):33-9
references.pmid: 8316295
references.citation: Nature. 1994 Mar 17;368(6468):215-21
references.pmid: 8145819
references.citation: Structure. 1997 Oct 15;5(10):1385-96
references.pmid: 9351812
references.citation: Annu Rev Immunol. 1995;13:587-622
references.pmid: 7612235
references.citation: J Comput Chem. 2009 Dec;30(16):2785-91
references.pmid: 19399780
references.citation: Hum Immunol. 1998 Oct;59(10):665-76
references.pmid: 9757949
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19329-34
references.pmid: 22084083
references.citation: Annu Rev Med. 2012;63:389-404
references.pmid: 21888515
references.citation: EMBO J. 2007 Apr 4;26(7):1972-83
references.pmid: 17363906
references.citation: PLoS One. 2011 Apr 14;6(4):e18662
references.pmid: 21533180
references.citation: In Silico Biol. 2005;5(5-6):505-28
references.pmid: 16268793
references.citation: Immunol Rev. 2007 Apr;216:81-92
references.pmid: 17367336
references.citation: Hum Immunol. 2000 Oct;61(10):1021-30
references.pmid: 11082515
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: Immunity. 2009 Dec 18;31(6):885-96
references.pmid: 20064447
references.citation: Cell. 1995 Mar 10;80(5):695-705
references.pmid: 7534214
references.citation: CNS Neurol Disord Drug Targets. 2012 Aug;11(5):528-44
references.pmid: 22583435
references.citation: Biochem J. 2008 Oct 15;415(2):183-96
references.pmid: 18800968
references.citation: Biopolymers. 2000-2001;56(4):257-65
references.pmid: 11754339
references.citation: J Phys Chem B. 2010 Jul 29;114(29):9608-16
references.pmid: 20590090
references.citation: Immunol Rev. 2012 Jan;245(1):227-38
references.pmid: 22168423
references.citation: Hepatology. 2011 Jun;53(6):1967-76
references.pmid: 21413052
references.citation: J Am Chem Soc. 2001 Jun 6;123(22):5221-30
references.pmid: 11457384
references.citation: Annu Rev Immunol. 1991;9:527-65
references.pmid: 1910688
references.citation: Bioinformatics. 2006 Jan 15;22(2):195-201
references.pmid: 16301204
references.citation: Mult Scler. 2011 Nov;17(11):1290-4
references.pmid: 21757535
references.citation: J Exp Med. 1998 Oct 19;188(8):1511-20
references.pmid: 9782128
references.citation: Curr Opin Immunol. 1995 Feb;7(1):85-96
references.pmid: 7772286
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3621-4
references.pmid: 12824380
references.citation: PLoS One. 2010 Jul 19;5(7):e11653
references.pmid: 20657836
references.citation: Biochim Biophys Acta. 2011 Feb;1812(2):265-74
references.pmid: 20637861
references.citation: J Chem Inf Model. 2007 Jan-Feb;47(1):122-33
references.pmid: 17238257
references.citation: J Immunol. 2009 Sep 1;183(5):3249-58
references.pmid: 19648278
references.citation: Immunol Res. 2010 Jul;47(1-3):56-64
references.pmid: 20066513
references.citation: Immunology. 2009 Dec;128(4):521-33
references.pmid: 19930042
references.citation: Nat Rev Immunol. 2009 Jun;9(6):408-17
references.pmid: 19444306
references.citation: J Mol Biol. 2011 Dec 2;414(3):385-400
references.pmid: 22019736
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13118-23
references.pmid: 21778406
references.citation: PLoS One. 2009;4(1):e4164
references.pmid: 19132105
references.citation: Cell. 1993 Jul 16;74(1):197-203
references.pmid: 8334703
references.citation: Nature. 1995 Nov 30;378(6556):457-62
references.pmid: 7477400
references.citation: Trends Biochem Sci. 2010 Oct;35(10):539-46
references.pmid: 20541943
references.citation: J Biol Chem. 2011 Nov 18;286(46):40163-73
references.pmid: 21937447