Bulletin of Mathematical Biology

, Volume 77, Issue 6, pp 1013–1045

Laplacian Dynamics with Synthesis and Degradation

• Inom Mirzaev
• David M. Bortz
Original Article

Abstract

Analyzing qualitative behaviors of biochemical reactions using its associated network structure has proven useful in diverse branches of biology. As an extension of our previous work, we introduce a graph-based framework to calculate steady state solutions of biochemical reaction networks with synthesis and degradation. Our approach is based on a labeled directed graph $$G$$ and the associated system of linear non-homogeneous differential equations with first-order degradation and zeroth-order synthesis. We also present a theorem which provides necessary and sufficient conditions for the dynamics to engender a unique stable steady state. Although the dynamics are linear, one can apply this framework to nonlinear systems by encoding nonlinearity into the edge labels. We answer an open question from our previous work concerning the non-positiveness of the elements in the inverse of a perturbed Laplacian matrix. Moreover, we provide a graph theoretical framework for the computation of the inverse of such a matrix. This also completes our previous framework and makes it purely graph theoretical. Lastly, we demonstrate the utility of this framework by applying it to a mathematical model of insulin secretion through ion channels in pancreatic $$\beta$$-cells.

Keywords

Laplacian dynamics Biochemical networks Synthesis and degradation Matrix-Tree Theorem Insulin secretion

List of abbreviations

$$\bar{\varvec{\rho }}^{C_{i}}$$

A column vector, which is the extension of $${\rho }^{C_{i}}$$, see Sect. 2

$$\varvec{\rho }^{G}$$

Kernel element of strongly connected graph $$G$$ calculated by MTT

$$\varDelta$$

A diagonal matrix with nonnegative entries

$$\frac{\mathrm{d}{\mathbf {x}}}{\mathrm{d}t}={\mathcal {L}}(G){\mathbf {x}}$$

Laplacian dynamics defined on the graph $$G$$

$$\frac{\mathrm{d}{\mathbf {x}}}{\mathrm{d}t}={\mathcal {L}}(G){\mathbf {x}} -D{\mathbf {x}}+{\mathbf {s}}$$

$${\mathbb {R}}^{m\times n}_{>0}$$

Set of all $$m\times n$$ matrices with strictly positive entries

$${\mathbf {s}}$$

Synthesis vector: a column vector with synthesis edges as entries

$${\mathbf {x}}_{\mathrm{s}}$$

$${\mathcal {L}}(G)$$

Laplacian matrix of the graph $$G$$

$${\mathcal {L}}_{i}$$

Perturbed matrix corresponding to SCC $$C_i, {\mathcal {L}}_{i}={\mathcal {L}}(C_{i})-\varDelta _{i}$$, where $$\varDelta _i$$ diagonal matrix corresponding to outgoing edges of SCC $$C_i$$; if $$C_i$$ is tSCC, then $$\varDelta _i\equiv 0$$

$$\mathcal {V}(X)$$

The set of vertices of graph $$X$$

$${\fancyscript{T}}$$

Directed spanning tree

$$\varTheta _i(G)$$

Set of DSTs of graph $$G$$ rooted at vertex $$i$$

$$a_i$$

Number of vertices in SCC $$C_i$$

$$A_{(ij)}$$

$$ij$$th minor of Laplacian matrix $$A$$ and is the determinant of $$(n-1)\times (n-1)$$ matrix that results from deleting row $$i$$ and column $$j$$

$$\mathrm{alg}_A(0)$$

Algebraic multiplicity of zero eigenvalue of matrix $$A$$

$$C[i]$$

SCC containing $$i$$

$$C[i]\preceq C[j]$$

SCC containing vertex $$j$$ can be reached from SCC containing $$i$$

$$C_{i}\preceq C_{j}$$

SCC $$C_{j}$$ can be reached from SCC $$C_{i}$$.

$$D$$

Degradation matrix, which is a diagonal matrix with degradation edges as diagonal entries

$$d_i$$

Label of degradation edge at vertex $$i$$

$$e_{ij}$$

an edge from vertex $$j$$ to vertex $$i$$

$$G$$

Labeled directed graph

$$G^{\star }$$

Complementary graph of $$G$$, which is formed by directing all synthesis and degradation edges to new vertex $$*$$

$$\mathrm{geo}_A(0)$$

Geometric multiplicity of zero eigenvalue of matrix $$A$$

$$i\Longleftrightarrow j$$

There exists a directed path from vertex $$i$$ to vertex $$j$$ and a directed path from vertex $$j$$ to vertex $$i$$

$$i\Longrightarrow j$$

There exists a directed path from vertex $$i$$ to vertex $$j$$

$$m_i$$

$$i$$th partial sum of $$c_i$$’s, $$m_{i}=\sum _{k=1}^{i}c_{k}$$

$$N$$

Lower-block diagonal submatrix of $${\mathcal {L}}(G)$$ corresponding to non-terminal SCCs

$$s_i$$

Label of synthesis edge at vertex $$i$$

$$T$$

Block diagonal submatrix of $${\mathcal {L}}(G)$$ corresponding to tSCCs

DST

Directed spanning tree

MTT

Matrix-Tree Theorem

SCC

Strongly connected component

SD dynamics

tSCC

Terminal strongly connected component

Notes

Acknowledgments

Funding for this research was supported in part by Grants NIH-NIGMS 2R01GM069438-06A2 and NSF-DMS 1225878. The authors would also like to thank Dr. Clayton Thompson (Systems Biology Group, Pfizer, Inc.) for his suggestion of the insulin synthesis example used in Sect. 5 and the two anonymous reviewers for their valuable comments on our manuscript.

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