Systems and methods for sampling and analysis of polymer conformational dynamics

Patent metadata

Field	Value
Publication number	US-10482991-B2
Application number	US-201314421490-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 17, 2012
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

Abstract

Systems and methods for searching conformation space of a polymer to determine a three-dimensional conformation of the polymer that satisfies a performance metric is provided. The polymer comprises a plurality of domains and at least a first hinge. Initial three-dimensional coordinates of the polymer are altered by pivoting the first domain with respect to the second domain about the first hinge thereby obtaining an altered set of three-dimensional coordinates for the polymer. In this altering, atoms within the first domain are held fixed with respect to each other and atoms within the second domain are also held fixed with respect to each other. The altered set of coordinates is scored against a performance metric. Additional instances of the altering and scoring are performed, if necessary, until the altered set of three-dimensional coordinates satisfy the performance metric.

First claim

I claim:

1. 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 {x 1A_init , . . . , x NA_init , x 1B_init , . . . , x MB_init , x 1C_init , . . . , x PC_init , . . . } for the protein, wherein
the polymer comprises a plurality of domains,
each respective x iA in {x 1A_init , . . . , x NA_init , x 1B_init , . . . , x MB_init , x 1C_init , . . . , x PC_init , . . . } is a three dimensional coordinate for an atom in a first domain in the plurality of domains,
each respective x iB in {x 1A_init , . . . , x NA_init , x 1B_init , . . . , x MB_init , x 1C_init , . . . , x PC_init , . . . } is a three dimensional coordinate for an atom in a second domain in the plurality of domains, and
each respective x iC in {x 1A_init , . . . , x NA_init , x 1B_init , . . . , x MB_init , x 1C_init , . . . , x PC_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 {x 1A_alt , . . . , x NA_alt , x 1B_alt , . . . , x MB_alt , x 1C_alt , . . . , x PC_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 {x 1A_alt , . . . , x NA_alt , x 1B_alt , . . . , x MB_alt, , x 1C_alt , . . . x PC_alt , . . . } satisfy the Metropolis criterion; and
(E) evaluating whether the altered set of three-dimensional coordinates {x 1A_alt , . . . , x NA_alt , x 1B_alt , . . . , x MB_alt , x 1C_alt , . . . , x PC_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.

2. The method of claim 1 , the method further comprising, prior to the altering (B):
determining the residues of the hinge on the basis of solvent accessibility and contacts made by the second plurality of residues in the initial set of three-dimensional coordinates.

3. The method of claim 1 , wherein the protein comprises a plurality of hinges, the plurality of hinges including the first hinge, wherein, for each respective hinge in the plurality of hinges, there is a corresponding pair of domains in the plurality of domains that pivot with respect to each other about the respective hinge, the method further comprising, prior to the altering (B):
determining the identity of the residues in each hinge in the plurality of hinges on the basis of solvent accessibility and contacts made by the second plurality of residues in the initial set of three-dimensional coordinates.

4. The method of claim 3 , wherein the altering further pivots a third domain with respect to a fourth domain in the plurality of domains about a second hinge in the plurality of hinges, wherein
all atoms within the third domain are held fixed with respect to each other during the pivoting of the third domain with respect to the fourth domain, and
all atoms within the fourth domain are held fixed with respect to each other during the pivoting of the third domain with respect to the fourth domain.

5. The method of claim 1 , wherein the scoring (C) comprises solving a loop closure problem for the first hinge to concurrently introduce alterations to some or all of a plurality of hinge parameters associated with the first hinge.

6. The method of claim 1 , wherein the first hinge comprises a plurality of hinge parameters and wherein fewer than 2(n−2) hinge parameters are altered in the pivoting of the first domain with respect to the second domain about the first hinge, wherein n is the number of residues in the second plurality of residues.

7. The method of claim 1 , the method further comprising, prior to the altering (B), determining the location of the first hinge by subjecting the initial set of three-dimensional coordinates to normal mode analysis.

8. The method of claim 1 , wherein the protein comprises a plurality of hinges, the plurality of hinges including the first hinge, wherein, for each respective hinge in the plurality of hinges, there is a corresponding pair of domains in the plurality of domains that pivot with respect to each other about the respective hinge, the method further comprising, prior to the altering (B), determining the identity of the residues in each hinge in the plurality of hinges by subjecting the initial set of three-dimensional coordinates to normal mode analysis.

9. The method of claim 1 , the method further comprising, prior to the altering (B), determining the residues of the polymer that comprise the first domain, the first hinge, and the second domain by principal component analysis.

10. The method of claim 1 , wherein the protein comprises a plurality of hinges, the plurality of hinges including the first hinge, wherein, for each respective hinge in the plurality of hinges, there is a corresponding pair of domains in the plurality of domains that pivot with respect to each other about the respective hinge, the method further comprising, prior to the altering (B), determining the identity of the residues in each hinge in the plurality of hinges is performed by principal component analysis.

11. The method of claim 1 , the method further comprising, prior to the altering (B), determining the residues of the protein that comprise the first domain, the first hinge, and the second domain by subjecting the initial set of three-dimensional coordinates to covariance analysis.

12. The method of claim 1 , wherein the protein comprises a plurality of hinges, the plurality of hinges including the first hinge, wherein, for each respective hinge in the plurality of hinges, there is a corresponding pair of domains in the plurality of domains that pivot with respect to each other about the respective hinge, the method further comprising, prior to the altering (B), determining the identity of the residues in each hinge in the plurality of hinges by subjecting the initial set of three-dimensional coordinates to covariance analysis.

13. The method of claim 1 , the method further comprising, prior to the altering (B): determining the residues of the protein that comprise the first domain, the first hinge, and the second dom

Assignees

• Zymeworks Inc

Inventors

• Dixit Surjit Bhimarao

Classifications

• G06F17/10

  Complex mathematical operations {(function generation by table look-up G06F1/03; evaluation of elementary functions by calculation G06F7/544)} · CPC title

• G16C10/00

  Computational theoretical chemistry, i.e. ICT specially adapted for theoretical aspects of quantum chemistry, molecular mechanics, molecular dynamics or the like · CPC title

• G16B15/00

  ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations or structure alignment · CPC title

• G16B5/00 Primary

  ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks · CPC title

• G16B5/30 Primary

  Dynamic-time models · CPC title