Patent Document ID: 7751987
Application ID: 09718425
Patent Status: 1

Claim One:
1. A computer-implemented method for predicting at least one amino acid sequence that folds into a specified three-dimensional (3D) structure of a predetermined reference protein or peptide, the at least one amino acid sequence having a biological activity the same as a biological activity of the reference protein or peptide; which method comprises the steps of: a) providing a coordinate set representing the backbone of the 3D structure; b) constructing a reduced virtual representation for the 3D structure provided in step (a), wherein in the reduced representation, each amino acid has a backbone portion and a side chain portion, the backbone portion of each amino acid being represented by a single sphere and the side chain of each amino acid being represented by one to three additional spheres; c) determining for each amino acid position along the virtual structure representation provided in step (b) its solvent accessibility; d) constructing an initial amino acid sequence by assigning for each amino acid position along the structure an amino acid residue selected randomly from a predefined group of amino acids having a solvent accessibility compatible with the solvent accessibility of the position; e) randomly selecting one or more positions along the sequence provided in step (d) and applying on each position a Monte-Carlo simulation in sequence space and rotamer space, the simulation comprising one or more scoring function calculating steps which include: i) randomly selecting one or more amino acid residues of the same solvent accessibility as that defined for the position to obtain a mutation; ii) for each of the one or more selected positions, calculating an energy difference delta E, between the amino acid residue at the position in the predetermined protein or peptide and each of the one or more selected amino acid residues provided in step (i) based on its the reduced virtual representation; iii) selecting a rotamer having a minimal delta E, or when more than one amino acid are manipulated simultaneously, selecting a rotamer combination having a minimal delta E; iv) accepting the mutation with the rotamer or rotamer combination selected in step (iii) if delta E<0; and v) assigning the amino acid residue or residues and their respective selected rotamer or rotamer combinations selected in step (iii) to the position(s) and moving to another position along the sequence; wherein the simulation steps are repeated until for each position along the sequence, the residue and residue's rotamer with the lowest energy score is selected, to obtain a virtually represented amino acid sequence with the lowest total energy score; f) expanding the reduced representation of the virtually represented amino acid sequence obtained in step (e) to its corresponding all-atom sequence representation thereby obtaining an amino acid sequence compatible with the structure of the predetermined protein or peptide; and g) outputting the expanded all-atom representation of the amino acid sequence obtained in step (f), wherein at least steps (b)-(f) are preformed on a sufficiently programmed computer.