Sensitivity analysis of biochemical systems using bond graphs

Abstract

The sensitivity of systems biology models to parameter variation can give insights into which parameters are most important for physiological function, and also direct efforts to estimate parameters. However, in general, kinetic models of biochemical systems do not remain thermodynamically consistent after perturbing parameters. To address this issue, we analyse the sensitivity of biological reaction networks in the context of a bond graph representation. We find that the parameter sensitivities can themselves be represented as bond graph components, mirroring potential mechanisms for controlling biochemistry. In particular, a sensitivity system is derived which re-expresses parameter variation as additional system inputs. The sensitivity system is then linearized with respect to these new inputs to derive a linear system which can be used to give local sensitivity to parameters in terms of linear system properties such as gain and time constant. This linear system can also be used to find so-called sloppy parameters in biological models. We verify our approach using a model of the Pentose Phosphate Pathway, confirming the reactions and metabolites most essential to maintaining the function of the pathway.