Systems and methods of sampling and analysis of conformational dynamics of polymers

摘要

A method of sampling and analyzing the conformational dynamics of polymers by searching the conformation space of a protein to determine if a three-dimensional conformation of the protein can bind more than one antigen into a plurality of target antigens, the protein comprising a first plurality of waste, the method comprising: in a computer system (11) having one or more processors (22) and memory (36) that stores one or more programs to be executed by the one or more processors (22): (A) obtain (402), from memory storage (36), an initial set of three-dimensional coordinates {x1A_init, ..., xNA_init, x1B_init, ..., xMB_init, ..., xPC_init, ...}; (46) corresponding to the atoms of the protein, wherein the protein comprises a plurality of domains, each respective xiA in {x1A_init, ..., xNA_init, x1B_init, ..., xMB_init, ..., xPC_init, .. .} (46) corresponds to 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, ..., xPC_init, ...} (46) corresponds to 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, ... , xPC_init, ...} (46) corresponds to a three-dimensional coordinate for an atom in a first hinge of the protein, where the first hinge comprises a second plurality of residues that is a subset of the first plurality of residues, where the protein is characterized by an ability for the first and second domains to pivot with each other around the first hinge; (B) alter (404), using a polymer generation module (50), the initial set of three-dimensional coordinates (46) of the protein by pivoting the first domain with respect to the second domain on the first hinge, thus obtaining an altered set of three-dimensional coordinates {x1A_alt, ..., xNA_alt, x1B_alt, ..., xMB_alt, ..., xPC_alt, ...} (56) for the protein, where all atoms within the first domain remain fixed between yes during the alteration, and all atoms within the second domain remain fixed with each other during the alteration; (C) punctuate (406), using a scoring module (52), a calculated potential energy of the altered set of three-dimensional coordinates (56) against a calculated potential energy of the initial three-dimensional coordinates for the protein with a Metropolis criterion, where, when the Metropolis criterion is met, the altered set of three-dimensional coordinates is accepted as the initial set of three-dimensional coordinates; (D) carry out (408), using the scoring module (52), additional instances of the alteration (B) and the scoring (C) until an energy of the altered set of three-dimensional coordinates {x1A_alt, ..., xNA_alt, x1B_alt, ..., xMB_alt, ..., xPC_alt, ...} (56) satisfies the Metropolis criterion; and (E) evaluate whether the altered set of three-dimensional coordinates {x1A_alt, ..., xNA_alt, x1B_alt, ..., xMB_alt, ..., xPC_alt, ...} can bind more than one antigen in the plurality of antigens target by attaching the altered set of three-dimensional coordinates {x1A_alt, ..., xNA_alt, x1B_alt, ..., xMB_alt, ..., xPC_alt, ...} to a model of the plurality of antigens.