Extended CADLIVE: a novel graphical notation for design of biochemical network maps and computational pathway analysis

Abstract

Biochemical network maps are helpful for understanding the mechanism of how a collection of biochemical reactions generate particular functions within a cell. We developed a new and computationally feasible notation that enables drawing a wide resolution map from the domain-level reactions to phenomenological events and implemented it as the extended GUI network constructor of CADLIVE (Computer-Aided Design of LIVing systEms). The new notation presents 'Domain expansion' for proteins and RNAs, 'Virtual reaction and nodes' that are responsible for illustrating domain-based interaction and 'InnerLink' that links real complex nodes to virtual nodes to illustrate the exact components of the real complex. A modular box is also presented that packs related reactions as a module or a subnetwork, which gives CADLIVE a capability to draw biochemical maps in a hierarchical modular architecture. Furthermore, we developed a pathway search module for virtual knockout mutants as a built-in application of CADLIVE. This module analyzes gene function in the same way as molecular genetics, which simulates a change in mutant phenotypes or confirms the validity of the network map. The extended CADLIVE with the newly proposed notation is demonstrated to be feasible for computational simulation and analysis.

Figure 1.

Improved graphical notation for regulators and reactions. The previous version of CADLIVE was improved to make clear the type of reactions. The regulator arrows are colored. The arrows of ‘homo association and modification’ and ‘homo association and modification with stoichiometric changes’ are revised. The reaction of ‘Set Modified from transition state’ is newly added.

Figure 2.

New notations in CADLIVE. These notations enable drawing a biochemical network at the domain or subunit level. (A) Protein P or RNA is expanded into two domains or two subunits (D1 and D2). (B) Virtual reactions and nodes. (C) The InnerLink arrow connects the real complex node (filled circle, source species) to the virtual node (open circle, target species) to illustrate the exact components of the real complex.

Figure 3.

Example models for presenting how to use the new notation. (A) Phosphorylation reactions at the domain level. The protein of Pro is expanded into the domains of A and B. 〈1〉 The virtual node indicates the state that Pro is phosphorylated on the B domain. 〈2〉 The virtual node indicates the state that Pro is phosphorylated on the A domain. 〈3〉 The real node of phosphorylated Pro (Pro-P) is produced. The InnerLink arrow (green) shows that the A domain is phosphorylated. 〈4〉 The real node of Pro-P-P is produced. The InnerLink arrow shows both the A and B domains are phosphorylated. 〈5〉 The real node of Pro-P is produced by dephosphorylation of Pro-P-P. The InnerLink arrow indicates the B domain is phosphorylated. (B) A phosphorus exchange reaction (Pro1 + Pro2-P -> Pro1-P + Pro2). 〈1〉 The virtual node indicates the state that Pro1 is phosphorylated. 〈2〉 The real node of Pro2-P is produced. 〈3〉 The InnerLink arrow indicates that the real node is Pro1-P. (C) Synthesis of the protein complex of Pro1:Pro2:Pro3. 〈1〉 The virtual node indicates the state that the B domain of Pro1 is bound to the E domain of Pro2. 〈2〉 The virtual node indicates the state that the D domain of Pro2 is bound to the F domain of Pro3. 〈3〉 The real node of Pro1:Pro2 is produced. The InnerLink arrow indicates that the B domain of Pro1 is bound to the E domain of Pro2. 〈4〉 The real node of Pro1:Pro2:Pro3 is produced. The InnerLinik arrow indicates that the D domain of Pro2 is bound to the F domain of Pro3.

Figure 4.

New notations for drawing modular architectures or unknown modules.

Figure 5.

A biochemical network map of the mammalian translation initiation system. This map is drawn by the extended CADLIVE GUI editor.

Figure 6.

A biochemical map of p53 drawn by the extended CADLIVE. Details of the map are clearly displayed by using the extended CADLIVE GUI editor.

Figure 7.

Demonstration of how the notation of the extended CADLIVE corresponds to that of the explicit MIM of Kohn's. (A) Kohn's notation. Species A is expanded into the D1 and D2 domains. The filled circle 〈1〉 is A-P-P whose D1 and D2 domains are phosphorylated. This map does not show how the product 〈1〉 is produced. (B) CADLIVE notation. Since CADLIVE must show how a product is produced from an elementary species, we assume that the product of A-P-P is produced by unknown factors of X, where we do not show any mechanism of how it is produced. The filled circle 〈2〉 indicates A-P-P where the D1 and D2 domains are phosphorylated. The filled circles of 〈1, 2〉 are the same species and the new notation of CADLIVE replaces the domain description by Kohn.

Figure 8.

Example models of the explicit, heuristic and combinatorial interpretation in CADLIVE. Tyree types of interpretation for the reactions are described in the side table. The number in the parentheses in the tables indicates the product species in the figures. For any RRE, interpretation is stated as, ‘yes’, ‘no’, or ‘maybe’. ‘Yes’ and ‘no’ mean that the reaction occurs and does not, respectively, which depends on the employed interpretation. In the heuristic column, ‘maybe’ means that it is not known whether the products marked by the number are synthesized. Although the notation of CADLIVE has originally been designed as an explicit MIM, it is possible to apply heuristic and combinatorial interpretation to a map of CADLIVE, because the CADLIVE notation is built based on Kohn's MIM. Note that the RREs generated by the CADLIVE editor correspond to the explicit MIM but does not to the heuristic and combinatorial MIMs.