Apparatus and method for structure-based prediction of amino acid sequences
AssigneeLonza Biologics PLC
InventorsJohan DESMET, Ignace LASTERS, Dominique VLIEGHE, Carlo BOUTTON, Philippe STAS
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Abstract
The present invention provides methods and apparatus for analyzing a protein structure.
Claims70
A method for analyzing a protein structure, the method being executed in a computer under the control of a program stored in the computer, and comprising the following steps:
- A) receiving, by the computer, a reference structure for a protein, whereby
- the said reference structure forms a representation of a three-dimensional structure of the said protein, and has a global energy Eref,
- the protein consists of a plurality of residue positions, each carrying a particular reference amino acid type in a specific reference conformation, and
- the protein residues are classified into a set of modeled residue positions and a set of conformationally fixed residues;
- B) substituting, by the computer, into the reference structure of step (A) a pattern, whereby
- the said pattern consists of one or more of the modeled residue positions defined in step (A), each carrying a particular amino acid residue type being placed at a specific residue position in the reference structure and adopting a specific conformation, and
- the one or more amino acid residue types of the said pattern are replacing the corresponding amino acid residue types present in the reference structure;
- C) optimizing, by the computer, the conformation of the reference structure of step (A) being substituted by the pattern of step (B), whereby
- a suitable protein structure optimization method based on a function allowing to assess the quality of a global protein structure, or any part thereof is used in combination with a suitable conformational search method, and
- the said structure optimization method is applied to all modeled residue positions defined in step (A) not being located at any of the pattern residue positions defined in step (B), with the proviso that said structure optimization method is not applied to any of said pattern residue positions;
- D) assessing, by the computer, the energetic compatibility of the pattern defined in step (B) within the context of the reference structure defined in step (A) being structurally optimized in step (C) with respect to the said pattern, by way of comparing the global energy E(p) of the substituted and optimized protein structure with the global energy Eref of the non-substituted reference structure to obtain an energetic compatibility object energy EECO(p);
- and
- E) generating and outputting, by the computer, to a display, a user, a readily accessible memory, another computer on a network, for another computer-readable medium, in the form of an energetic compatibility object (ECO), a value reflecting the said energetic compatibility of the pattern together with information forming a full description of the three-dimensional structure comprising the substituted pattern;
- wherein the reference structure of step (A) is received from a database of protein structures.
A type-dependent, topology-specific solvation method for the assignment of a set of energetic solvation terms to a set of residue types, depending on the degree of solvent exposure of their respective rotamers at the considered residue positions in a protein structure, wherein:
- first, each residue type at a given residue position in a specific rotameric state is substituted into the protein structure and its accessible surface area (ASA) is calculated,
- next, a class assignment occurs on the basis of the percentage ASA of the residue side chain in the protein structure compared to the maximal ASA of the same side chain being shielded from the solvent only by its own main-chain atoms, and
- finally an appropriate type- and topology-specific energy, ETTS(T,C), for the considered pattern element is retrieved from a table of TS values, using the pattern type (T) and class (C) indices.
A computing device for computing a type-dependent, topology-specific solvation for the assignment of a set of energetic solvation terms to a set of residue types, depending on the degree of solvent exposure of their respective rotamers at the considered residue positions in a protein structure, comprising:
- Means for substituting each residue type at a given residue position in a specific rotameric state into the protein structure and its accessible surface area (ASA) is calculated,
- Means for a class assigning on the basis of the percentage ASA of the residue side chain in the protein structure compared to the maximal ASA of the same side chain being shielded from the solvent only by its own main-chain atoms, and
- Means for retrieving an appropriate type- and topology-specific energy, ETTS(T,C), for the considered pattern element from a table of TTS values in the form of a data structure, using the pattern type (T) and class (C) indices.
A computer program product to be utilized with a computer system having a memory and a processor for computing a type-dependent, topology-specific solvation for the assignment of a set of energetic solvation terms to a set of residue types, depending on the degree of solvent exposure of their respective rotamers at the considered residue positions in a protein structure, comprising:
- Instruction means for substituting each residue type at a given residue position in a specific rotameric state into the protein structure and its accessible surface area (ASA) is calculated,
- Instruction means for a class assigning on the basis of the percentage ASA of the residue side chain in the protein structure compared to the maximal ASA of the same side chain being shielded from the solvent only by its own main-chain atoms, and
- Instruction means for retrieving an appropriate type- and topology-specific energy, ETTS(T,C), for the considered pattern element from a table of TTS values in the form of a data structure, using the pattern type (T) and class (C) indices.
Dependencies are inferred from the claim text.