Method, computing routine, device for predicting properties of mhc/peptide complexes, and data and peptides produced therefrom

Abstract

The present invention relates to a method for structure-based prediction of properties of peptides and peptide analogs in complex with major histocompatibility (MHC) class I and class II molecules. The said properties mainly relate to the three-dimensional structure of an MHC/peptide complex and the binding affinity of a peptide for an MHC receptor. The invention further relates to a computer program and a device therefor. The invention further relates to data produced by a method of the invention. The invention further relates to peptides and peptide analogs predicted to bind to target-MHC molecules. The present invention thus relates to the field of immunology, with possible applications in manufacture of vaccinates, de-immunization of proteins, and manufacture of therapeutic agents, especially immuno-therapeutic agents.

1 - 32 . (canceled) 
     
     
         33 . A representation of one or more peptide backbone structures of one or more peptides that interact with a major histocompatibility (MHC) class I or class II molecule, obtained by a method comprising
 (a) providing an amino acid sequence of a polypeptide of interest;   (b) preparing one or more overlapping putative immunogenic peptide fragments of said polypeptide of interest;   (c) receiving a representation of a complete or partial three-dimensional structure of said MHC class I or class II molecule;   (d) obtaining an ensemble of conformational representations of peptide backbone structures of said putative immunogenic peptide fragments, said conformational representations located within the binding site of said MHC molecule;   (e) modeling the side chains of said peptide backbone structures of said ensemble in relation to said MHC molecule, thereby obtaining an ensemble of modeled MHC/peptide complexes;   (f) evaluating the binding properties of said putative immunogenic peptides for said MHC molecule, by using a scoring function which combines at least:
 f1) average binding energy component obtained by evaluating one or more components of the potential energy of each complex of the ensemble of step (e); 
 f2) conformational entropy component obtained by evaluating the conformational entropy for the complete ensemble of each modeled MHC/peptide complex of step (e); and 
   (g) inferring from the results obtained in (f), one or more putative immunogenic peptides that bind to said MHC molecule;   
       thereby obtaining a representation of one or more peptide backbone structures of one or more peptides that interact with a major histocompatibility (MHC) class I or class II molecule. 
     
     
         34 . A computer program comprising computing routines, stored on a computer readable medium for predicting the binding affinity of a peptide for a major histocompatibility (MHC) class I or class II molecule, said routines comprising:
 a) receiving a representation of a complete or partial three-dimensional structure of a MHC class I or class II molecule,   b) obtaining an ensemble of conformational representations of peptide backbone structures of said peptide, said conformational representations located within the binding site of said MHC molecule,   c) modeling the side-chains of said peptide for each peptide backbone structure of said ensemble in relation to said MHC molecule, thereby obtaining an ensemble of modeled MHC/peptide complexes, and   d) evaluating the binding properties of said peptide for said MHC molecule, by using scoring function which combines at least:
 d1) average binding energy component obtained by evaluating one or more components of the potential energy of each complex of the ensemble of step c), and 
 d2) conformational entropy component obtained by evaluating the conformational entropy for the complete ensemble of modeled MHC/peptide complexes of step c). 
   
     
     
         35 . (canceled) 
     
     
         36 . A computer program according to  claim 34 , wherein said peptide backbone structures are obtained by computer modeling or by retrieval from a database. 
     
     
         37 . A device for predicting the binding affinity of a peptide for a major histocompatibility (MHC) class I or class II molecule, comprising means for:
 a) receiving a representation of a complete or partial three-dimensional structure of a MHC class I or class II molecule,   b) obtaining an ensemble of conformational representations of peptide backbone structures of said peptide, said conformational representations located within the binding site of said MHC molecule,   c) modeling the side-chains of said peptide for each peptide backbone structure of said ensemble in relation to said MHC molecule, thereby obtaining an ensemble of modeled MHC/peptide complexes, and   d) evaluating the binding properties of said peptide for said MHC molecule, by using scoring function which combines at least:
 d1) average binding energy component obtained by evaluating one or more components of the potential energy of each complex of the ensemble of step c), and 
 d2) conformational entropy component obtained by evaluating the conformational entropy for the complete ensemble of modeled MHC/peptide complexes of step c). 
   
     
     
         38 . A peptide which binds major histocompatibility (MHC) class I or class II molecules, said peptide being obtainable by a method comprising
 (a) providing an amino acid sequence of a polypeptide of interest;   (b) preparing one or more overlapping putative immunogenic peptide fragments of said polypeptide of interest;   (c) receiving a representation of a complete or partial three-dimensional structure of said MHC class I or class II molecule;   (d) obtaining an ensemble of conformational representations of peptide backbone structures of said putative immunogenic peptide fragments, said conformational representations located within the binding site of said MHC molecule.   (e) modeling the side chains of said peptide backbone structures of said ensemble in relation to said MHC molecule, thereby obtaining an ensemble of modeled MHC/peptide complexes;   (f) evaluating the binding properties of said putative immunogenic peptides for said MHC molecule, by using a scoring function which combines at least:
 f1) average binding energy component obtained by evaluating one or more components of the potential energy of each complex of the ensemble of step (e); 
 f2) conformational entropy component obtained by evaluating the conformational entropy for the complete ensemble of each modeled MHC/peptide complex of step (e); 
   (g) inferring from the results obtained in (f), one or more putative immunogenic peptides that bind to said MHC molecule; and   (h) preparing one or more of said putative immunogenic peptides of said polypeptide of interest.   
     
     
         39 . An peptide which binds major histocompatibility (MHC) class I or class II molecules, said peptide being obtained by a method comprising
 (a) providing an amino acid sequence of a polypeptide of interest;   (b) preparing one or more overlapping putative immunogenic peptide fragments of said polypeptide of interest;   (c) receiving a representation of a complete or partial three-dimensional structure of said MHC class I or class II molecule;   (d) obtaining an ensemble of conformational representations of peptide backbone structures of said putative immunogenic peptide fragments, said conformational representations located within the binding site of said MHC molecule.   (e) modeling the side chains of said peptide backbone structures of said ensemble in relation to said MHC molecule, thereby obtaining an ensemble of modeled MHC/peptide complexes;   (f) evaluating the binding properties of said putative immunogenic peptides for said MHC molecule, by using a scoring function which combines at least:
 f1) average binding energy component obtained by evaluating one or more components of the potential energy of each complex of the ensemble of step (e); 
 f2) conformational entropy component obtained by evaluating the conformational entropy for the complete ensemble of each modeled MHC/peptide complex of step (e); 
   (g) inferring from the results obtained in (f), one or more putative immunogenic peptides that bind to said MHC molecule; and   (h) preparing one or more of said putative immunogenic peptides of said polypeptide of interest.   
     
     
         40 . A nucleic acid encoding a peptide as defined in  claim 38  or  39 . 
     
     
         41 . A nucleic acid of at least 15 nucleotides in length specifically hybridizing with the nucleic acid of  claim 40 . 
     
     
         42 . An antibody specifically recognizing a peptide according to  claim 38  or  39 . 
     
     
         43 . An antibody specifically recognizing a nucleic acid according to  claim 40 . 
     
     
         44 . A method for producing a peptide according to  claim 38  or  39  comprising:
 (a) culturing host cells comprising a nucleic acid encoding the peptide under conditions allowing the expression of the peptide, and, 
 (b) recovering the produced peptide from the culture. 
 
     
     
         45 . The peptide according to  claim 38  or  39  formulated as a medicament. 
     
     
         46 . The nucleic acid according to  claim 40  formulated as a medicament. 
     
     
         47 . The representation of  claim 33  comprising an indication of the MHC molecule associated with said representation. 
     
     
         48 . An antibody specifically recognizing a nucleic acid according to  claim 41 . 
     
     
         49 . The nucleic acid according to  claim 41  formulated as a medicament.