Method for Affinity Scoring of Peptide/Protein Complexes

Abstract

The present invention is related to a quantitative structure-based affinity scoring method for peptide/protein complexes. More specifically, the present invention comprises a method that operates on the basis of a highly specific force field function (e.g. CHARMM) that is applied to all-atom structural representations of peptide/receptor complexes. Peptide side-chain contributions to total affinity are scored after detailed rotameric sampling followed by controlled energy refinement. The method of the invention further comprises a de novo approach to estimate dehydration energies from the simulation of individual amino acids in a solvent box filled with explicit water molecules and applying the same force field function as used to evaluate peptide/receptor complex interactions.

1 . A method for determining an affinity score of a protein/ligand complex, wherein said score is solely based on structural data and a force field, this method comprising:
 (a) calculating a ligand-solvent interaction energy from a structural representation of the ligand placed in a box with explicit solvent molecules;   (b) calculating a ligand-protein interaction energy from a structural representation of the ligand placed in the binding site of the protein; and   (c) calculating said affinity score by subtracting the ligand-solvent interaction energy of step (a) from the ligand-protein interaction energy of step (b).   
     
     
         2 . The method of  claim 1 , further comprising
 calculating a conformational strain energy for the protein/ligand representation of step (b); and   calculating said affinity score by subtracting the ligand-solvent interaction energy of step (a) and the conformational strain energy from the ligand-protein interaction energy of step (b).   
     
     
         3 . The method of  claim 2  wherein the conformational strain energy of step (c) is calculated as the difference between, the sum of conformational energies of the ligand and protein in an unbound reference state and the sum of the conformational energies of the ligand and the protein in the protein/ligand representation of step (b). 
     
     
         4 . The method of  claim 1 , wherein the protein/ligand representation of step (b) is derived from an experimentally determined structure. 
     
     
         5 . The method of  claim 1 , wherein the protein/ligand representation of step (b) is generated by computer modeling. 
     
     
         6 . The method of  claim 5 , wherein the computer modeling comprises an amino acid side-chain modeling step. 
     
     
         7 . The method of  claim 5 , wherein the computer modeling comprises an energy minimization step. 
     
     
         8 . The method of  claim 1 , wherein the representation of the ligand in the solvent box of step (a) is derived from an experimentally determined structure. 
     
     
         9 . The method of  claim 1 , wherein the representation of the ligand in the solvent box of step (a) is generated by computer modeling. 
     
     
         10 . The method of  claim 9 , wherein the computer modeling comprises an amino acid side-chain modeling step. 
     
     
         11 . The method of  claim 9 , wherein the computer modeling comprises an energy minimization step. 
     
     
         12 . The method of  claim 1 , wherein the protein to which the ligand binds is a receptor such as a MHC receptor or an antibody. 
     
     
         13 . The method of  claim 1 , wherein the ligand is a peptide, a small molecule or a pharmacophore. 
     
     
         14 . The method of  claim 1 , wherein the solvent in step (a) exclusively consists of water molecules. 
     
     
         15 . The method of  claim 1 , wherein calculating the affinity score further comprises combining desolvation energy and protein-ligand complex energy, and wherein both desolvation energy and protein-ligand complex energy are derived from the same force field. 
     
     
         16 . The method of  claim 1 , wherein calculating the affinity score further comprises combining desolvation energy and receptor-ligand complex energy, and wherein both desolvation energy and protein-ligand complex energy are derived from the same force field. 
     
     
         17 . The method of  claim 1 , wherein calculating the affinity score further comprises determining the affinity score for anchor residues in a protein-ligand complex. 
     
     
         18 . The method of  claim 17 , wherein the protein-ligand complex comprises a MHC receptor/ligand complex. 
     
     
         19 . A method for determining an affinity score of a protein/ligand complex, wherein said score is solely based on structural data and a force field, this method comprising
 (a) calculating a ligand-solvent interaction energy from a structural representation of the ligand placed in a box with explicit solvent molecules;   (b) calculating a ligand-protein interaction energy from a structural representation of the ligand placed in the binding site of the protein;   (c) calculating a conformational strain energy for the protein/ligand representation of step (b); and   (d) calculating said affinity score by subtracting the ligand-solvent interaction energy of step (a) and the conformational strain energy of step (c) from the ligand-protein interaction energy of step (b).   
     
     
         20 . The method of  claim 2 , wherein the conformational strain energy of step (c) is calculated as the difference between the sum of conformational energies of the ligand and protein in an unbound reference state and the sum of the conformational energies of the ligand and the protein in the protein/ligand representation of step (b).