structural immunoinformatics – two case studies
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Medical University of SofiaFaculty of Pharmacy. Structural Immunoinformatics – two case studies. M. Atanasova , I. Dimitrov, A. Patronov, I. Doytchinova. Regional Conference in Supercomputing Applications in Science and Industry, 20-21 Sept. 2011, Sunny Beach, Bulgaria. - PowerPoint PPT PresentationTRANSCRIPT
Structural Immunoinformatics – two case studies
M. Atanasova, I. Dimitrov, A. Patronov, I. Doytchinova
Medical University of Sofia Faculty of Pharmacy
Regional Conference in Supercomputing Applications in Science and Industry, 20-21 Sept. 2011, Sunny Beach, Bulgaria
Medical University of Sofia Faculty of Pharmacy
Immunoinformastic Approaches:
Sequence - based Structure - based
peptide pIC50exp
ILDPFPVTV 8.654ALDPFPPTV 8.170VLDPFPITV 8.139................ .......FLDPFPATV 8.270
Affinity = f (Chemical Structure)Motif-based, QMs, ANN, SVM
Affinity = f (Interaction energy)Molecular docking
Molecular dynamics
Immunoinformatics (Computational Immunology, Theoretical Immunology)
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Boophilusmicroplus tick.
Ticks are hematophagous parasites that feed on variety of domestic animals. B. microplus tick:
• a hard tick;• transmits lethal pathogens;•causes disease and death.
Collaborator: University of Pretoria, SA
Aim:to predict peptides originating from B. microplus and binding with high affinity to murine MHC class II proteins IAd and IEd.
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Approaches used
Sequence - based
Structure - based
MHCPred and RANKPEP servers for MHC class II binding prediction
Molecular docking calculations
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Selection of high immunogenic B. microplus proteins by VaxiJen server.
Presentation of the selected proteins as sets of overlapping peptides.
1.
2.
B. Microplus numberProtein peptides
Contig2828 59Contig7420 93CK181624 61
Selection of input X-ray structures of complexes of murine MHC II protein with a peptide.
Ova/IAd (pdb code: 2iad)HB/IEk (pdb code:1iea)
Homology modelingof IEk to IEd structure
3. Optimization of complexes of each peptide with each MHC II protein.
Dockingcalculations
biding site - 6Å; Chemscore – scoring function; fixed protein and peptide backbone; ranking – by score; GOLD v.5.0.2.
Workflow:
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Binding affinity prediction to IAd by MHCPred and RANKPEP
MHCPred: Predicted binders with IC50 < 50 nMare highlighted in green.
RANKPEP: Predicted binders with binding threshold:
7.10 are highlighted in purple.
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Binding affinity prediction to IAd and IEd by Molecular docking
IAd IEdThe top 2 best clusters of binders are highlighted in magenta.
Medical University of Sofia Faculty of Pharmacy
Case study 1: T-cell epitope prediction of proteins from Boophilus microplus
Peptides selected for further experimental studies
Medical University of Sofia Faculty of Pharmacy
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
Aim: to generate quatitative matrices (QMs) for prediction of peptides binding to SLA-1
IntestinalDiarrhea
RespiratoryCoughingSore Throat
PhyschologicalLethargyLack of appetite
Swine influenza symptoms
NasopharynxSneezingMucous: nose/eyesSystemicFeverWeight lossPoor growth
Swine Influenza in pigs:- An acute respiratory disease;- High morbidity depending on the immune status;- Can results in important economic losses.
CReSACentre de Recerca en Sanitat Animal
Modeled proteins:
SLA-1*0101 SLA-1*0401SLA-1*0501 SLA-1*1101
7 anchor positions X 19 aa = 133 + 1 original ligand = 134 peptides
biding site - 6Å; Chemscore – scoring function; fixed protein and ligand apart from the residues from the tested peptide position; ranking – by lowest RMS; GOLD v.5.0.2.
normalization of the binding energies and compilation into QMs.
P1 P2P3
P5
P6P7
P9
Medical University of Sofia Faculty of Pharmacy
Workflow:
1. Homology modeling of SLA-1 from HLA*0201 (pdb:3pwj).
2. Construction of combinatorial library of peptides.
3. Molecular docking of peptides to SLA proteins.
4. Forming of docking score-based QMs (DS-QMs).
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
Medical University of Sofia Faculty of Pharmacy
Workflow:
1. Homology modeling of SLA-1 from HLA*0201 (pdb:3pwj).
2. Construction of combinatorial library of peptides.
3. Molecular docking of peptides to SLA proteins.
4. Forming of docking score-based QMs (DS-QMs).
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
Combinatorial library peptide avr score normalized PKYVKQNTLKLAT - 71.47 + 0.456 PKXVKQNTLKLAT - 63.72 - 0.123 PKYXKQNTLKLAT … … PKYVKXNTLKLAT … … PKYVKQNXLKLAT … … PKYVKQNTXKLAT … … PKYVKQNTLKXAT … … PKYVKQNTLKLXT … …
aa\pocket 1 2 3 5 6 7 9
A … … … … … … … C … … … … … … … D … … … … … … … E … … … … … … … … … … … … … … …
QM
0101 – Asn0101 - Leu 0501 - Trp
Medical University of Sofia Faculty of Pharmacy
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
SLA allele Pocket 2 profile P2 accepts0101 Tyr9, Ala24, Val34, Met45, Glu63, Lys66, Gln67 Leu, Met, Asn
0501 Ser9, Ala24, Val34, Met45, Glu63, Lys66, Gln67 Trp, Leu, Phe
0401 Tyr9, Ala24, Val34, Met45, Glu63, Asn66, Val67 Leu, Met, Thr
1101 Ser9, Glu24, Val34, Met45, Glu63, Arg66, Val67 Leu, Met, Ile
0401 - Met 1101 - Met
Medical University of Sofia Faculty of Pharmacy
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
SLA allele Pocket 2 profile P2 accepts0101 Tyr9, Ala24, Val34, Met45, Glu63, Lys66, Gln67 Leu, Met, Asn
0501 Ser9, Ala24, Val34, Met45, Glu63, Lys66, Gln67 Trp, Leu, Phe
0401 Tyr9, Ala24, Val34, Met45, Glu63, Asn66, Val67 Leu, Met, Thr
1101 Ser9, Glu24, Val34, Met45, Glu63, Arg66, Val67 Leu, Met, Ile
Medical University of Sofia Faculty of Pharmacy
Case study 2: Prediction of peptide binding to Swine Leukocyte Antigen (SLA-1)
binders to SLA-1*0101>gi|91177888|gb|ABE27153.1| hemagglutinin [Influenza A virus (A/swine/Spain/53207/2004(H1N1))]MEAKLFVLFCAFTALKADTICVGYHANNSTDTVDTILEKNVTVTHSVNLLENSHNGKLCSLNGKAPLQLGNCNVAGWILGNPECDLLLTANSWSYIIETSNSKNGACYPGEFADYEELREQLSTVSSFERFEIFPKATSWPNHETTKGTTVACSHSGANSFYRNLLWIVKKGNSYPKLSKSYTNNKGKEVLVIWGVHHPPTDSNQQTLYQNNHTYVSVGSSKYYQRFTPEIVARPKVREQAGRMNYYWTLLDQGDTITFEATGNLIAPWHAFALNKGSSSGIMMSDAHVHNCTTKCQTPHGALKSNLPFQNVHPITIGECPKYVKSTQLRMATGLRNIPSTQSRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQIAIDGISNKVNSVIEKMNIQFTSVGKEFNNLEKRIENLNKKVDDGFLDVWTYNAELLILLENERTLDFHDFNVKNLYEKVKSQLRNNAKEIGNGCFEFYHKCDNECMESVKNGTYNYPRYSEESKLNREEIDGVKLESVGVHQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
binders to SLA-1*0401>gi|91177888|gb|ABE27153.1| hemagglutinin [Influenza A virus (A/swine/Spain/53207/2004(H1N1))]MEAKLFVLFCAFTALKADTICVGYHANNSTDTVDTILEKNVTVTHSVNLLENSHNGKLCSLNGKAPLQLGNCNVAGWILGNPECDLLLTANSWSYIIETSNSKNGACYPGEFADYEELREQLSTVSSFERFEIFPKATSWPNHETTKGTTVACSHSGANSFYRNLLWIVKKGNSYPKLSKSYTNNKGKEVLVIWGVHHPPTDSNQQTLYQNNHTYVSVGSSKYYQRFTPEIVARPKVREQAGRMNYYWTLLDQGDTITFEATGNLIAPWHAFALNKGSSSGIMMSDAHVHNCTTKCQTPHGALKSNLPFQNVHPITIGECPKYVKSTQLRMATGLRNIPSTQSRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQIAIDGISNKVNSVIEKMNIQFTSVGKEFNNLEKRIENLNKKVDDGFLDVWTYNAELLILLENERTLDFHDFNVKNLYEKVKSQLRNNAKEIGNGCFEFYHKCDNECMESVKNGTYNYPRYSEESKLNREEIDGVKLESVGVHQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
binders to SLA-1*0501>gi|91177888|gb|ABE27153.1| hemagglutinin [Influenza A virus (A/swine/Spain/53207/2004(H1N1))]MEAKLFVLFCAFTALKADTICVGYHANNSTDTVDTILEKNVTVTHSVNLLENSHNGKLCSLNGKAPLQLGNCNVAGWILGNPECDLLLTANSWSYIIETSNSKNGACYPGEFADYEELREQLSTVSSFERFEIFPKATSWPNHETTKGTTVACSHSGANSFYRNLLWIVKKGNSYPKLSKSYTNNKGKEVLVIWGVHHPPTDSNQQTLYQNNHTYVSVGSSKYYQRFTPEIVARPKVREQAGRMNYYWTLLDQGDTITFEATGNLIAPWHAFALNKGSSSGIMMSDAHVHNCTTKCQTPHGALKSNLPFQNVHPITIGECPKYVKSTQLRMATGLRNIPSTQSRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQIAIDGISNKVNSVIEKMNIQFTSVGKEFNNLEKRIENLNKKVDDGFLDVWTYNAELLILLENERTLDFHDFNVKNLYEKVKSQLRNNAKEIGNGCFEFYHKCDNECMESVKNGTYNYPRYSEESKLNREEIDGVKLESVGVHQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
binders to SLA-1*1101>gi|91177888|gb|ABE27153.1| hemagglutinin [Influenza A virus (A/swine/Spain/53207/2004(H1N1))]MEAKLFVLFCAFTALKADTICVGYHANNSTDTVDTILEKNVTVTHSVNLLENSHNGKLCSLNGKAPLQLGNCNVAGWILGNPECDLLLTANSWSYIIETSNSKNGACYPGEFADYEELREQLSTVSSFERFEIFPKATSWPNHETTKGTTVACSHSGANSFYRNLLWIVKKGNSYPKLSKSYTNNKGKEVLVIWGVHHPPTDSNQQTLYQNNHTYVSVGSSKYYQRFTPEIVARPKVREQAGRMNYYWTLLDQGDTITFEATGNLIAPWHAFALNKGSSSGIMMSDAHVHNCTTKCQTPHGALKSNLPFQNVHPITIGECPKYVKSTQLRMATGLRNIPSTQSRGLFGAIAGFIEGGWTGMIDGWYGYHHQNEQGSGYAADQKSTQIAIDGISNKVNSVIEKMNIQFTSVGKEFNNLEKRIENLNKKVDDGFLDVWTYNAELLILLENERTLDFHDFNVKNLYEKVKSQLRNNAKEIGNGCFEFYHKCDNECMESVKNGTYNYPRYSEESKLNREEIDGVKLESVGVHQILAIYSTVASSLVLLVSLGAISFWMCSNGSLQCRICI
SIV proteins screenedto predict SLA binders:- hemagglutinin (HA)- nucleocapsid protein (NP)- matrix protein 1 (M1)- polymerase PB1 (PB1)
Thank you for your attention!