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Method for Affinity Scoring of Peptide/Protein Complexes

a technology of peptide/protein complex and affinity scoring, which is applied in the field of quantitative structure-based affinity scoring method for ligand/protein complex, can solve the problems of small-scale flexibility due to bond angle bending, additional difficulties in deviating from ideal rotameric states, and limited conformational flexibility, and achieves the effect of convenient transfer

Inactive Publication Date: 2008-12-18
ALGONOMICS
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  • Summary
  • Abstract
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AI Technical Summary

Benefits of technology

[0021](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). Advantageously the conformational strain energy of step (c) herein is calculated as the difference between, on the one hand, the sum of the conformational energies of the ligand and protein in an unbound reference state and, on the other hand, the sum of the conformational energies of the ligand and the protein in the protein / ligand representation of step (b). It is thus possible to calculate conformational strain energies sufficiently fast and in a way that they are compatible with the force field used.
[0033]The scoring functions of the invention are easily transferable to different protein / ligand complexes, as demonstrated below, without the need of reparameterisation.

Problems solved by technology

Structure-based binding studies face two major technical barriers.
Yet, deviation from ideal rotameric states and small-scale flexibility due to bond angle bending present additional difficulties.
In such cases, conformational flexibility is limited, which facilitates structure-based analysis.
The second problem is how to derive accurate binding affinities from experimental or modeled representations.
Further, ligand / receptor interfaces are rarely optimally packed and can include multiple water molecules.
Here, it is not uncommon that methods performing relatively well on data similar to the training set are significantly less accurate on more divergent datasets or must even be retrained.
Transferability therefore remains an important and delicate matter.
Possible contributions like contact-based potentials, weight-adapted conformational energy terms, shape complementarity, hydrophobic corrections and different entropical components may yield good results but poor transferability.
Because of the danger of over-parameterization, erroneous assignment of either false or redundant contributions is likely.
Underparameterization, in particular of conformational strain, is another problem.

Method used

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  • Method for Affinity Scoring of Peptide/Protein Complexes
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Examples

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example 1

Model Preparation

[0071]The preparation of model complexes depends on the availability of template structures in the Protein Data Bank. If one or more tertiary structures for a given HLA subtype are known, a selection is made primarily on the basis of crystallographic resolution. Additional criteria such as R-factor, length of the bound peptide, experimental affinity of the latter, width of the binding groove, etc., are considered as well. For A2 1DUZ was selected as the starting template. Since no exact templates were available for A1, A24 and B7, these had to be modeled. First, a structure was selected from the PDB using the same criteria as for A2, considering also the sequence similarity of receptor residues in contact with the peptide. The following template structures were chosen: 1HSB (type Aw68) for A1, 1DUZ (type A2) for A24 and 1A9E (type B35) for B7. The coordinates for amino acid residues 1-181 (the α1α2-domain) and the extant peptide were extracted from the files. Water ...

example 2

Peptide Binding Assays

[0074]IC50 values were determined using a cell-based assay, largely according to van der Burg et al, Hum Immunol 1995; 44:189-98 and Kessler et al, Hum Immunol 2003; 64:245-55. Briefly, immortalized B-cells displaying HLA-A*0201 or HLA-A*2402 homozygously (VOSE EBV (A*0201, B*4402, Cw*0501 / 0711) and HATT EBV (A*2402, B*4801, Cw*0801 / 1202) are stripped of their self peptides, followed by equilibrium binding of test peptide in competition with fluorescent reference peptide (FLPSDC(5Fluorescein)FPSV for A2 and RYLKC(5Fluorescein)QQLL for A24). A 10-point concentration range of test peptide is used for each measurement, typically in 2-fold increments from 62.5 nM to 32 μM, in a constant background of 30 nM reference peptide. Adapted ranges were used for excellent binders (minimal concentration 7.8 nM) and weak binders (maximal concentration 128 μM). 50% inhibitory concentrations (IC50-values) were calculated as averages obtained from at least 3 independent measurem...

example 3

Affinity Scoring of HLA-A2 Complexes

[0075]HLA-A*0201 (A2) is one of the most extensively studied peptide binding receptor molecules. It is known to show a strong preference for peptide ligands having Leu at position P2 and Val or Leu at P9. The modeling of all 20 natural amino acid residues at the anchor positions P2 and P9 was performed systematically for the three pAla-A2 models. FIG. 2 shows the averaged scoring values for position P2 in pAla-A2. Total affinity scores have been dissected into the three major energetic components: desolvation energy, side-chain / complex interaction (including interactions with all pAla residues but the mutated one) and “local strain” (including strain within the mutant residue). All values are expressed in units of kcal / mol, i.e. the units of the force field equations.

[0076]A striking observation from FIG. 2 is that direct side-chain / complex interactions are very large: for 50% of the residues they lie in the range −15 to −20 kcal / mol. It is seen t...

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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.

Description

[0001]This application is a National Stage of PCT / BE2005 / 000052, filed on Apr. 21, 2005, which claims priority to EPO patent 04447103.5 filed on Apr. 21, 2004, which applications are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention is related to a quantitative structure-based affinity scoring method for ligand / protein complexes such as 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...

Claims

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Application Information

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IPC IPC(8): G01N33/68G16B15/30G16B20/30G16B20/50
CPCG06F19/16G06F19/18G16B15/00G16B20/00G16B20/30G16B20/50G16B15/30
Inventor DESMET, JOHANMEERSSEMAN, GEERTBOUTONNET, NATHALIEPLETINCKX, JURGENDE CLERCQ, KRISTALASTERS, IGNACE
Owner ALGONOMICS
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