Conceptual Model-based Systems Biology: mapping knowledge and discovering gaps in the mRNA transcription cycle

Abstract

We propose a Conceptual Model-based Systems Biology framework for qualitative modeling, executing, and eliciting knowledge gaps in molecular biology systems. The framework is an adaptation of Object-Process Methodology (OPM), a graphical and textual executable modeling language. OPM enables concurrent representation of the system's structure-the objects that comprise the system, and behavior-how processes transform objects over time. Applying a top-down approach of recursively zooming into processes, we model a case in point-the mRNA transcription cycle. Starting with this high level cell function, we model increasingly detailed processes along with participating objects. Our modeling approach is capable of modeling molecular processes such as complex formation, localization and trafficking, molecular binding, enzymatic stimulation, and environmental intervention. At the lowest level, similar to the Gene Ontology, all biological processes boil down to three basic molecular functions: catalysis, binding/dissociation, and transporting. During modeling and execution of the mRNA transcription model, we discovered knowledge gaps, which we present and classify into various types. We also show how model execution enhances a coherent model construction. Identification and pinpointing knowledge gaps is an important feature of the framework, as it suggests where research should focus and whether conjectures about uncertain mechanisms fit into the already verified model.

Figure 1. OPM entities with their symbols, definitions and operation semantics.

Figure 2. OPM procedural links: links connecting an object or state with a process.

These links represent process pre/postcondition object set.

Figure 3. OPM structural links: links connecting an object with an object.

Theses links represent structural hierarchies and characteristics.

Figure 4. An example of OPM query capability: mRNA search.

Figure 5. Complex generic model and example.

(A) A generic model of the structure of a Complex. The object Complex consists of at least one (denoted by “1..m”) Protein, which consists at least one Domain, each of which, in turn, consists at least one Binding Site. (B) The Complex Polymerase II with one of its proteins, Rpb1 and its 26 Repeat Sets with their structure. The balloons include explanation of the OPM semantics.

Figure 6. Generic link object and example.

(A) A generic simple Link example. The object Link connects two binding sites A and B. The Link object can be created by a binding process and consumed by a dissociation process. (B) The TFIIF-TFIIB Complex is composed of a TFIIF Complex, a TFIIB Complex and a TFIIF-to-TFIIB Complex Link Set.

Figure 7. Binding/Dissociation molecular function, modeling templates and example.

Figure 8. Transporting molecular function, modeling template and example.

Figure 9. Catalyzing molecular function, modeling templates and example.

Figure 10. Complex formation: the process of molecular binding exemplified on Rpb4/7 to Polymerase II binding.

(A) Rpb4/7 and Polymerase II Binding process (B) Rpb4/7 and Polymerase II Binding process zoomed into its sub-processes, Link Set Generating and Polymerase II–and-Rpb4/7 Complex Assembling.

Figure 11. The transcription process bi-modal representation.

(A) The Transcription process model. (B) The corresponding automatically-generated Object-Process Language (OPL).

Figure 12. The execution of the transcription model.

Here shown a snapshot of the Elongation process being executed (and therefore highlighted in purple), and the mRNA changes states from capped into elongated. See supplemental movie SV1 for Re-initiation process non-deterministic execution.

Figure 13. Pre-initiation complex formation and initiation model.

In this example we apply the Catalyzing - Substrate Changed modeling template for modeling serine 5 phosphorylation (surrounded by dashed square) by TFIIH Kinase. TFIIB Kinase is still conjectured and therefore highlighted in grey.

Figure 14. Example of two errors found during model execution.

The transcription model execution halts during the Pol II.CTD.Serine 5 Phosphorylation process with errors presented in the lowest frame (see Video S2). The first error is a missing object error and the second is an incorrect state error.