Spacio-temporal determination of polypeptide structure

A method of analyzing and ranking epitope structures of a target polypeptide for targeting by a therapeutic, the method comprising:

• a. providing a polypeptide sequence of a target polypeptide;
• b. computing a protein homology model from the polypeptide sequence;
• c. applying a molecular dynamics (MD) simulation to the protein homology model to obtain a 3D protein ensemble of the target polypeptide;
• d. constructing a graph network by assigning individual alpha carbon atoms in the 3D protein ensemble as nodes and interactions between neighboring alpha carbon backbone atoms as graph edges;
• e. identifying a plurality of epitope structures in the polypeptide sequence using a model that is trained to identify epitope structures from the graph network;
• f. calculating index scores for the plurality of epitope structures in the polypeptide sequence, wherein the index scores are calculated based on at least two of:
• a structural prominence parameter, a disorder parameter, or a conservation parameter of the epitope, wherein:
• i. the structural prominence parameter is derived from the 3D protein ensemble;
• ii. the disorder parameter is determined by a root mean square fluctuation of an alpha carbon in a backbone of the target polypeptide in the 3D protein ensemble;
• iii. the conservation parameter is calculated based on conservation of at least two amino acid residues in a multiple sequence alignment comprising the polypeptide sequence of the target polypeptide;
• and
• iv. the index scores are proportional to the structural prominence parameter and the conservation parameter, and are inversely proportional to the disorder parameter;
• and
• g. ranking an epitope structure among the plurality of epitope structures having the highest index scores in a ranking of index scores, thereby generating a ranked range of epitope structures of the target polypeptide available for subsequent selection for targeting with the therapeutic;
• h. selecting the epitope structure with the highest ranked index score from the ranked range of epitope structures of the target polypeptide for generating a paratope structure;
• i. generating the paratope structure for the therapeutic that is predicted to bind to the epitope structure;
• wherein the therapeutic comprises the paratope structure;
• and
• j. making the therapeutic by a process that comprises chemical synthesis or expression in a host cell.