Peptide Binding motif Height of a column equal to I Relative height of a letter is p High information positions HLA-A0201
NetMHC ANN and 68 PSSM Covering Human, Primate and Mouse MHC Predictions can be made for 8-11 mer petides
HLA polymorphism < 50 HLA alleles are characterized by binding data Reliable MHC class I binding predictions (NetMHC-3.0) for 60 HLA A and B molecules No methods for HLA-C, and HLA-E Long way to over 1500!
HLA polymorphism Few human beings will share the same set of HLA alleles –Different persons will react to a pathogen infection in a non-similar manner A CTL based vaccine must include epitopes specific for each HLA allele in a population –A CTL based vaccine must consist of ~1000 HLA class I epitopes and ~5000 class II epitopes
The IMGT/HLA Sequence Database currently encompass more than 1500 HLA class I proteins Source: HLA polymorphism
Supertypes. What are they good for? Alleles with in supertypes present the same set of peptides! Is this really so? –Less that 50% of A6802 binders will bind to A0201! –Less than 33% of A0201 binders will bind to A6802!
The truth about supertypes! A2 A24 A26 A3 A1
HLA- A*3001 HLA- A*3002
NetMHCpan - the method NetMHC NetMHCpan
Pan-specific method The contact residues are defined as being within 4.0 Å of the peptide in any of a representative set of HLA-A and -B structures with nonamer peptides. Only polymorphic residues from A, B, and C alleles are included Pseudo-sequence consisting of 34 amino acid residues. Include polymorphic residues in potential contact with the bound peptide
Example Peptide Amino acids of HLA pockets HLA Aff VVLQQHSIA YFAVLTWYGEKVHTHVDTLVRYHY A SQVSFQQPL YFAVLTWYGEKVHTHVDTLVRYHY A SQCQAIHNV YFAVLTWYGEKVHTHVDTLVRYHY A LQQSTYQLV YFAVLTWYGEKVHTHVDTLVRYHY A LQPFLQPQL YFAVLTWYGEKVHTHVDTLVRYHY A VLAGLLGNV YFAVLTWYGEKVHTHVDTLVRYHY A VLAGLLGNV YFAVWTWYGEKVHTHVDTLLRYHY A VLAGLLGNV YFAEWTWYGEKVHTHVDTLVRYHY A VLAGLLGNV YYAVLTWYGEKVHTHVDTLVRYHY A VLAGLLGNV YYAVWTWYRNNVQTDVDTLIRYHY A
Predictions for novel HLA alleles
Can accuracy be predicted?
HLA-C, HLA-E HLA-C*0102 HLA-E*0101 HLA-E HLA-C
And now to animals Work by PhD Student Ilka Hoff
Are chimpanzees like Human?
Prediction Primate MHCs Can we predict binding specificities from non-human primates using netMHCpan method trained on human specificity data only?
NetMHCpan-1.1 More than 1200 HLA-A and B alleles. C alleles will come soon! Predictions for 8-11 mer peptides
HLA class II polymorphism More than 2000 HLA class II allele combinations –HLA-DR –HLA-DQ –HLA-DP Only data for 14 of the more than 500 known HLA-DR allele (< 3%) No data for HLA-DQ and HLA-DP
Class II MHC binding MHC class II binds peptides in the class II antigen presentation pathway Binds peptides of length 9-18 (even whole proteins can bind!) Binding cleft is open Binding core is 9 aa
MHC class II binding motif mer peptides ~10 30 combinations Monte Carlo simulations can do it
NetMHC-IIpan Train on peptide:MHC sequences –As for the NetMHCpan for class I Need to identify peptide core! –Use SMM-align
MHC pseudo sequence The contact residues are defined as being within 4.0 Å of the peptide in any of a representative set of HLA-DR, -DQ, and DP structures with peptides. Only polymorphic residues are included Pseudo-sequence consisting of 25 amino acid residues. Include polymorphic residues in potential contact with the bound peptide