Systems and methods for sampling and analysis of polymer conformational dynamics

A method of sampling and analysis of protein conformational dynamics by searching the conformation space of a protein to determine whether a three-dimensional conformation of the protein can co-engage each antigen in a plurality of target antigens, the protein comprising a first plurality of residues, the method comprising:

• at a computer system having one or more processors and memory storing one or more programs to be executed by the one or more processors:
• (A) obtaining from the memory an initial set of three-dimensional coordinates {x1A_init, . . . , xNA_init, x1B_init, . . . , xMB_init, x1C_init, . . . , xPC_init, . . . } for the protein, wherein
• the polymer comprises a plurality of domains,
• each respective xiA in {x1A_init, . . . , xNA_init, x1B_init, . . . , xMB_init, x1C_init, . . . , xPC_init, . . . } is a three dimensional coordinate for an atom in a first domain in the plurality of domains,
• each respective xiB in {x1A_init, . . . , xNA_init, x1B_init, . . . , xMB_init, x1C_init, . . . , xPC_init, . . . } is a three dimensional coordinate for an atom in a second domain in the plurality of domains, and
• each respective xiC in {x1A_init, . . . , xNA_init, x1B_init, . . . , xMB_init, x1C_init, . . . , xPC_init, . . . } is a three dimensional coordinate for an atom in a first hinge of the protein, wherein the first hinge comprises a second plurality of residues that is a subset of the first plurality of residues, wherein the protein is characterized by an ability for the first and second domain to pivot with respect to each other about the first hinge;
• (B) altering the initial set of three-dimensional coordinates of the protein by pivoting the first domain with respect to the second domain about the first hinge thereby obtaining an altered set of three-dimensional coordinates {x1A_alt, . . . , xNA_alt, x1B_alt, . . . , xMB_alt, x1C_alt, . . . , xPC_alt, . . . } for the protein, wherein
• all atoms within the first domain are held fixed with respect to each other during the altering, and
• all atoms within the second domain are held fixed with respect to each other during the altering;
• (C) scoring, using a scoring module, a calculated potential energy of the altered set of coordinates versus a calculated potential energy of the initial three-dimensional coordinates for the protein with a Metropolis criterion, wherein, when the Metropolis criterion is satisfied, the altered set of three-dimensional coordinates is accepted as the initial set of three-dimensional coordinates;
• (D) performing additional instances of the altering (B) and the scoring (C) until an energy of the altered set of three-dimensional coordinates {x1A_alt, . . . , xNA_alt, x1B_alt, . . . , xMB_alt,, x1C_alt, . . . xPC_alt, . . . } satisfy the Metropolis criterion;
• and
• (E) evaluating whether the altered set of three-dimensional coordinates {x1A_alt, . . . , xNA_alt , x1B_alt, . . . , xMB_alt, x1C_alt, . . . , xPC_alt, . . . } can co-engage each antigen in the plurality of target antigens by docking the altered set three-dimensional coordinates to a model of the plurality of antigens.