Abstract
Circuit simulation is a powerful methodology to generate differential mathematical models. Due to its highly accurate modeling capability, circuit simulation can be used to investigate interactions between the parts and processes of a cellular system. Circuit simulation has become a core technology for the field of electrical engineering, but its application in biology has not yet been fully realized. As a case study for evaluating the more advanced features of a circuit simulation tool called Advanced Design System (ADS), we collected and modeled laboratory data for iron metabolism in mouse kidney cells for a H ferritin (HFt) receptor, T cell immunoglobulin and mucin domain-2 (TIM-2). The internal controlling parameters of TIM-2 associated iron metabolism were extracted and the ratios of iron movement among cellular compartments were quantified by ADS. The differential model processed by circuit simulation demonstrated a capability to identify variables and predict outcomes that could not be readily measured by in vitro experiments. For example, an initial rate of uptake of iron-loaded HFt (Fe-HFt) was 2.17 pmol per million cells. TIM-2 binding probability with Fe-HFt was 16.6%. An average of 8.5 min was required for the complex of TIM-2 and Fe-HFt to form an endosome. The endosome containing HFt lasted roughly 2 h. At the end of endocytosis, about 28% HFt remained intact and the rest was degraded. Iron released from degraded HFt was in the labile iron pool (LIP) and stimulated the generation of endogenous HFt for new storage. Both experimental data and the model showed that TIM-2 was not involved in the process of iron export. The extracted internal controlling parameters successfully captured the complexity of TIM-2 pathway and the use of circuit simulation-based modeling across a wider range of cellular systems is the next step for validating the significance and utility of this method.
Highlights
There have been both classical and advanced uses of analogous electronic circuit concepts in evaluating biological systems
In this study, multiple T cell immunoglobulin and mucin domain-2 (TIM-2) associated iron metabolic processes: iron uptake, storage, and export were modeled simultaneously based on a direct implementation from the Agilent Advanced Design System (ADS) circuit simulator software
Internal controlling parameters for TIM-2 iron pathway were extracted by ADS based on in vitro data collected from mice kidney TCMK-1 TIM-2 and vector cells
Summary
There have been both classical and advanced uses of analogous electronic circuit concepts in evaluating biological systems. For more than several decades, both animal and plant physiologists have used models such as Ohm’s Law to model environmental response (Janes, 1970; Meier et al, 2003). A modern challenge has been to discover and interrelate cellular dynamics with higher-level outcomes (Kitano, 2002a). Biochemical systems theory (BST) provides a conceptual foundation for differential analysis of the functional requirements and design principles of a viable cell (Savageau, 1972, 1979, 2001). Electrical circuits are subject to differential analysis of their linear and nonlinear components (McAdams and Shapiro, 1995).
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