Whole-cell kinetic models have been used for several years to model the binding and trafficking behavior of ligands and receptors within cells. The principles of mass action kinetics are used in the development of these models, and recently, there has been success in using these models for identifying design criteria by which to engineer proteins. To further contribute to the development of these models and the identification of relationships between molecular-level changes and cellular-level trafficking, we have derived a whole-cell kinetic model using a more physics-based approach. One distinguishing feature of our kinetic model is the use of general principles, such as surface area arguments and Le Chatelier's principle, to model certain steps in the cellular trafficking pathway, thereby removing the need to introduce additional rate constants. The other distinguishing feature is the incorporation of a statistical thermodynamic framework for predicting the distribution of a ligand in the endosome, which is an important parameter in our model. Although the current version of the theory incorporates a simple model for the electrostatic and excluded-volume interactions that operate between the ligand and the endosome, this theoretical framework can be extended in the future to incorporate more rigorous models for electrostatics and other interactions. However, even with the current version of our model, we have been able to reasonably predict in vitro trafficking data for the Fc ligand/FcRn receptor system. We have also been able to identify a parameter that shows improved correlation with in vivo half-life trends when compared to the current state-of-the-art correlation.

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