# US 2021/0241846 A1 · Multicellular metabolic models and methods

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- Number: US 2021/0241846 A1
- Document ID: US20210241846A1
- Status: Published application
- Kind: A1
- Application number: 17/018,629
- Filed: 2020-09-11
- Published: 2021-08-05
- Earliest claimed: 2002-03-29
- Assignees: Genomatica, Inc.
- Applicants: Genomatica, Inc.
- Inventors: Imandokht Famili; Christophe H. Schilling
- Web page: https://patentgrep.com/patent/US20210241846A1

## CPC

- G16B 5/00: ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G01N 33/5008: {for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics}
- G16B 20/20: Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection
- G16B 50/00: ICT programming tools or database systems specially adapted for bioinformatics
- G16B 50/10: Ontologies; Annotations
- G16C 20/30: Prediction of properties of chemical compounds, compositions or mixtures
- G01N 2500/10: involving cells
- G16B 20/00: ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- G16C: COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE

## Abstract

The invention provides a computer readable medium or media, having: (a) a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) a constraint set for said plurality of reactions for said first, second and third data structures, and (e) commands for determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells. The first, second and third data structures also can include a plurality of data structures. Additionally provided is a method for predicting a physiological function of a multicellular organism. The method includes: (a) providing a first data structure relating a plurality of reactants to a plurality of reactions from a first cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (b) providing a second data structure relating a plurality of reactants to a plurality of reactions from a second cell, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (c) providing a third data structure relating a plurality of intra-system reactants to a plurality of intra-system reactions between said first and second cells, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product; (d) providing a constraint set for said plurality of reactions for said first, second and third data structures; (e) providing an objective function, and (f) determining at least one flux distribution that minimizes or maximizes an objective function when said constraint set is applied to said first and second data structures, wherein said at least one flux distribution is predictive of a physiological function of said first and second cells.

## Claims

### Claim at position 1

1-60. (canceled)

### Claim 61

A computer-implemented method for predicting a physiological function of single-celled organisms, comprising:
(a) providing on a computer a first data structure comprising a first stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of first reactions from a first single-celled organism, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, stoichiometric coefficients of the first stoichiometric matrix relating said substrate and said product, wherein at least one reactant in said plurality of reactants or at least one reaction in said plurality of reactions is annotated with an assignment to a subsystem or compartment;
(b) providing on the computer a second data structure comprising a second stoichiometric matrix having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of second reactions from a second single-celled organism, each of said reactions comprising a reactant identified as a substrate of the reaction and a reactant identified as a product of the reaction, stoichiometric coefficients of the second stoichiometric matrix relating said substrate and said product, wherein at least one reactant in said plurality of reactants or at least one reaction in said plurality of reactions is annotated with an assignment to a subsystem or compartment;
(c) providing on the computer a third data structure comprising a third stoichiometric matrix or elements in the first or second stoichiometric matrices having rows and columns of elements that correspond to stoichiometric coefficients of a plurality of intra-system reactions between said first and second single-celled organisms and an intra-cellular system of said first or second single-celled organisms, each of said intra-system reactions comprising a reactant identified as a substrate of the reaction located in one of the first or second single-celled organisms or in the intra-cellular system and a reactant identified as a product of the reaction located in another of the first and second single-celled organisms or in the intra-cellular system, stoichiometric coefficients of the third stoichiometric matrix relating said substrate and said product;
(d) providing on the computer a constraint set for said plurality of reactions for said first, second and third data structures, the constraint set specifying an upper or lower boundary of flux through each of the reactions described in the first, second, and third stoichiometric matrices;
(e) defining on the computer an objective function to be a linear combination of fluxes through the reactions described in the first, second, and third stoichiometric matrices that optimizes cell growth, reproduction, apoptosis, energy production, production of a hormone or extracellular component, a mechanical property, or maintenance of biomass composition and growth rate;
(f) determining on the computer at least one flux distribution for said plurality of first, second and intra-system reactions across said first single-celled organism, said second single-celled organism, and said intra-cellular system by (i) identifying a plurality of flux vectors that each satisfy the stoichiometric matrix and satisfy the constraint set and (ii) identifying at least one linear combination of the flux vectors that minimizes or maximizes the objective function; and
(g) providing output to a user of said at least one flux distribution determined in step (f), wherein said at least one flux distribution is predictive of a physiological function of said first and second single-celled organisms.

### Claim 62 (depends on 61)

The method of claim 61, wherein said first data structure comprises a first reaction network.

### Claim 63 (depends on 61)

The method of claim 61, wherein said second data structure comprises a second reaction network.

### Claim 64 (depends on 61)

The method of claim 61, wherein said first or second data structures comprise a plurality of reaction networks.

### Claim 65 (depends on 61)

The method of claim 61, further comprising providing on the computer one or more fourth data structures comprising one or more fourth stoichiometric matrices and one or more fourth constraint sets, each fourth data structure relating a plurality of reactants to a plurality of one or more third reactions from one or more third single-celled organisms, each of said reactions comprising a reactant identified as a substrate of the reaction, a reactant identified as a product of the reaction and a stoichiometric coefficient relating said substrate and said product.

### Claim 66 (depends on 65)

The method of claim 65, wherein said one or more fourth data structures comprises a plurality of data structures.

### Claim 67 (depends on 66)

The method of claim 66, wherein said plurality of data structures comprise a data structure for a plurality of different single-celled organisms.

### Claim 68

The method of 65, wherein said one or more third single-celled organism comprises at least 4 single-celled organisms, 5 single-celled organisms, 6 single-celled organisms, 7 single-celled organisms, 8 single-celled organisms, 9 single-celled organisms, 10 single-celled organisms, 100 single-celled organisms, 1000 single-celled organisms, 5000 single-celled organisms, 10,000 single-celled organisms or more.

### Claim 69 (depends on 61)

The method of claim 61, wherein said first and second single-celled organisms comprise eukaryotic cells.

### Claim 70 (depends on 61)

The method of claim 61, wherein said first and second single-celled organisms comprise prokaryotic cells.

### Claim 71 (depends on 61)

The method of claim 61, further comprising accessing with the computer a gene database having information characterizing an associated gene.

### Claim 72 (depends on 61)

The method of claim 61, wherein at least one of said reactions is a regulated reaction.

### Claim 73 (depends on 72)

The method of claim 72, wherein said constraint set includes a variable constraint for said regulated reaction.

### Claim 74 (depends on 61)

The method of claim 61, wherein said intra-system reactions comprise a reactant or reactions selected from the group consisting of a bicarbonate buffer system, an ammonia buffer system, a hormone, a signaling molecule, a vitamin, a mineral or a combination thereof.

### Claim 75 (depends on 61)

The method of claim 61, wherein a plurality of reactions is annotated to indicate a plurality of associated genes and wherein said gene database comprises information characterizing said plurality of associated genes.