Method of generating non-naturally occuring protein models
OwnerEldon G. Emberly, Chao Tang +1inventors
InventorsEldon G. Emberly, Chao Tang, Ned S. Wingreen
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Abstract
The invention provides new designable protein backbone configurations. The configurations are produced by a computer implemented method which includes the steps of: (a) specifying a fixed number of secondary structural elements having a set of dihedral angle pairs (b) generating a set of stacks having secondary structural elements; and (c) evaluating designability of the stacks.
Claims26
A computer implemented method to generate a model representation of a class of proteins specified by the length, three dimensional orientation and connectivity of secondary structures, comprising the steps of:
- generating a set of three dimensional protein model configurations each composed of an arrangement of a connected sequence of predetermined secondary structural elements selected from the group of alpha-helices and beta-sheet elements, with predetermined lengths and orders of these elements along a protein chain;
- computing the free energy of each residue sequence for each model configuration, wherein the energy functions are selected from (i) the interaction energies between residues nearby in the configuration but not adjacent along the chain, and (ii) the hydrophobic salvation energy;
- considering the set of all possible residue sequences for a given model configuration, and determining the configuration with the lowest free energy among the set of protein model configurations for each residue sequence, wherein a residue sequence consists of residues selected from the amino-acid residues found in natural proteins;
- and
- determining the protein model configurations which satisfy lowest energy for a large number of sequences to produce a list of model configurations that satisfy predetermined criteria;
- and
- screening the model configurations that satisfy said criteria against a database of known existing protein configurations to select those configurations not known in nature as a class model representation.
A protein comprising three helices coiled with a right-handed twist atop a fourth helix, all having backbone dihedral angles of about {φ, ψ}={−60, −50}.
A protein comprising four helices, with a cloverleaf connectivity and helices 1 and 3 atop helices 2 and 4, all having backbone dihedral angles of about {φ, ψ}={−60, −50}.
A computer system for providing a database of protein structures useful for chemical and pharmaceutical laboratory research comprising:
- a memory for storing (i) a database of naturally occurring protein structures, and (ii) a set of generated protein structures satisfying predetermined designability criteria;
- a thermally novel protein structure identification procedure including machine executable instructions for
- (a) generating a class of proteins based upon predetermined designability criteria;
- (b) comparing the structural characteristics of each member of said class with said database to identify similar generated protein structures;
- and
- (c) storing the identified protein structures which satisfy predetermined satisfiability criteria.
Computer software resident on a computer readable medium including a library of protein designs specified by composition, length, and three dimensional orientation of the chains of amino acid sequences, the software comprising instructions for:
- processing a three dimensional configuration of receptor and ligand molecules that is of laboratory testing interest;
- determining a class of designable proteins satisfying the three dimensional configuration criteria;
- computing the potential energy of each model configuration;
- for a given model configuration, considering the set of all possible residue sequences and determining the lowest-energy configuration among the set of protein model configurations, wherein a sequence consists of residues selected from the amino-acid residues found in natural proteins;
- and wherein the energy functions are selected from the interaction energies between residues nearby in the configuration but not adjacent along the polymer, and the hydrophobic solvation energy;
- and
- determining the protein model configurations which satisfy lowest energy for large number of sequences.
Dependencies are inferred from the claim text.