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Design Space Toolbox V2: Automated Software Enabling a Novel Phenotype-Centric Modeling Strategy for Natural and Synthetic Biological Systems.

Lomnitz JG, Savageau MA - Front Genet (2016)

Bottom Line: We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy.The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach.In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count, and a negative channel that decreases the count.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of California, Davis Davis, CA, USA.

ABSTRACT
Mathematical models of biochemical systems provide a means to elucidate the link between the genotype, environment, and phenotype. A subclass of mathematical models, known as mechanistic models, quantitatively describe the complex non-linear mechanisms that capture the intricate interactions between biochemical components. However, the study of mechanistic models is challenging because most are analytically intractable and involve large numbers of system parameters. Conventional methods to analyze them rely on local analyses about a nominal parameter set and they do not reveal the vast majority of potential phenotypes possible for a given system design. We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy. Instead, this approach relies on architectural features of the model to identify the phenotypic repertoire and then predict values for the parameters that yield specific instances of the system that realize desired phenotypic characteristics. Here, we present a collection of software tools, the Design Space Toolbox V2 based on the System Design Space method, that automates (1) enumeration of the repertoire of model phenotypes, (2) prediction of values for the parameters for any model phenotype, and (3) analysis of model phenotypes through analytical and numerical methods. The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach. We illustrate the power of these new tools by applying them to a synthetic gene circuit that can exhibit multi-stability. We then predict values for the system parameters such that the design exhibits 2, 3, and 4 stable steady states. In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count, and a negative channel that decreases the count. This example shows the power of these new automated methods to rapidly identify behaviors of interest and efficiently predict parameter values for their realization. These tools may be applied to understand complex natural circuitry and to aid in the rational design of synthetic circuits.

No MeSH data available.


Conceptual model for the design of a gene regulatory circuit exhibiting positive autogenous regulation. (A) A cartoon of the proposed design showing an autogenously activated gene regulator in green. The regulator is fused with a dimerization domain shown in purple. Homodimerization leads to the active form of the regulator. A repressor, represented by the red capsule, sterically hinders activator binding. (B) Binding to a second protein with a complementary dimerization domain leads to a heterodimer that is degraded by cellular proteases or other machinery. (C) Abstract representation of the gene circuit design. The activator X1, which corresponds to the green protein in the cartoon, autogenously activates its own expression. The bimolecular reaction of X1 and X2 leads to the heterodimer, which corresponds to the blue-green protein in the cartoon, that is then degraded. The repressor X3, which corresponds to the red protein in the cartoon, blocks binding of the activtor to its DNA control region.
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Figure 1: Conceptual model for the design of a gene regulatory circuit exhibiting positive autogenous regulation. (A) A cartoon of the proposed design showing an autogenously activated gene regulator in green. The regulator is fused with a dimerization domain shown in purple. Homodimerization leads to the active form of the regulator. A repressor, represented by the red capsule, sterically hinders activator binding. (B) Binding to a second protein with a complementary dimerization domain leads to a heterodimer that is degraded by cellular proteases or other machinery. (C) Abstract representation of the gene circuit design. The activator X1, which corresponds to the green protein in the cartoon, autogenously activates its own expression. The bimolecular reaction of X1 and X2 leads to the heterodimer, which corresponds to the blue-green protein in the cartoon, that is then degraded. The repressor X3, which corresponds to the red protein in the cartoon, blocks binding of the activtor to its DNA control region.

Mentions: Mathematical modeling of biochemical phenomena usually begins with the synthesis of available knowledge from the literature and experimental data that together provide a foundation for generating a particular hypothesis. The hypothesis is usually represented by a conceptual model that contains qualitative information regarding the key components and their interactions, typically visualized using some sort of diagram. An example of a conceptual model for a simple gene regulatory circuit is represented in Figure 1.


Design Space Toolbox V2: Automated Software Enabling a Novel Phenotype-Centric Modeling Strategy for Natural and Synthetic Biological Systems.

Lomnitz JG, Savageau MA - Front Genet (2016)

Conceptual model for the design of a gene regulatory circuit exhibiting positive autogenous regulation. (A) A cartoon of the proposed design showing an autogenously activated gene regulator in green. The regulator is fused with a dimerization domain shown in purple. Homodimerization leads to the active form of the regulator. A repressor, represented by the red capsule, sterically hinders activator binding. (B) Binding to a second protein with a complementary dimerization domain leads to a heterodimer that is degraded by cellular proteases or other machinery. (C) Abstract representation of the gene circuit design. The activator X1, which corresponds to the green protein in the cartoon, autogenously activates its own expression. The bimolecular reaction of X1 and X2 leads to the heterodimer, which corresponds to the blue-green protein in the cartoon, that is then degraded. The repressor X3, which corresponds to the red protein in the cartoon, blocks binding of the activtor to its DNA control region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4940394&req=5

Figure 1: Conceptual model for the design of a gene regulatory circuit exhibiting positive autogenous regulation. (A) A cartoon of the proposed design showing an autogenously activated gene regulator in green. The regulator is fused with a dimerization domain shown in purple. Homodimerization leads to the active form of the regulator. A repressor, represented by the red capsule, sterically hinders activator binding. (B) Binding to a second protein with a complementary dimerization domain leads to a heterodimer that is degraded by cellular proteases or other machinery. (C) Abstract representation of the gene circuit design. The activator X1, which corresponds to the green protein in the cartoon, autogenously activates its own expression. The bimolecular reaction of X1 and X2 leads to the heterodimer, which corresponds to the blue-green protein in the cartoon, that is then degraded. The repressor X3, which corresponds to the red protein in the cartoon, blocks binding of the activtor to its DNA control region.
Mentions: Mathematical modeling of biochemical phenomena usually begins with the synthesis of available knowledge from the literature and experimental data that together provide a foundation for generating a particular hypothesis. The hypothesis is usually represented by a conceptual model that contains qualitative information regarding the key components and their interactions, typically visualized using some sort of diagram. An example of a conceptual model for a simple gene regulatory circuit is represented in Figure 1.

Bottom Line: We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy.The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach.In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count, and a negative channel that decreases the count.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of California, Davis Davis, CA, USA.

ABSTRACT
Mathematical models of biochemical systems provide a means to elucidate the link between the genotype, environment, and phenotype. A subclass of mathematical models, known as mechanistic models, quantitatively describe the complex non-linear mechanisms that capture the intricate interactions between biochemical components. However, the study of mechanistic models is challenging because most are analytically intractable and involve large numbers of system parameters. Conventional methods to analyze them rely on local analyses about a nominal parameter set and they do not reveal the vast majority of potential phenotypes possible for a given system design. We have recently developed a new modeling approach that does not require estimated values for the parameters initially and inverts the typical steps of the conventional modeling strategy. Instead, this approach relies on architectural features of the model to identify the phenotypic repertoire and then predict values for the parameters that yield specific instances of the system that realize desired phenotypic characteristics. Here, we present a collection of software tools, the Design Space Toolbox V2 based on the System Design Space method, that automates (1) enumeration of the repertoire of model phenotypes, (2) prediction of values for the parameters for any model phenotype, and (3) analysis of model phenotypes through analytical and numerical methods. The result is an enabling technology that facilitates this radically new, phenotype-centric, modeling approach. We illustrate the power of these new tools by applying them to a synthetic gene circuit that can exhibit multi-stability. We then predict values for the system parameters such that the design exhibits 2, 3, and 4 stable steady states. In one example, inspection of the basins of attraction reveals that the circuit can count between three stable states by transient stimulation through one of two input channels: a positive channel that increases the count, and a negative channel that decreases the count. This example shows the power of these new automated methods to rapidly identify behaviors of interest and efficiently predict parameter values for their realization. These tools may be applied to understand complex natural circuitry and to aid in the rational design of synthetic circuits.

No MeSH data available.