Modelling multivalent effects for multimeric ligand and receptor complexes

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Dr. Antal Péter
Department of Measurement and Information Systems

The general objective of the project was to design a framework to process hematopoietic lineage commitment using artificial signaling hubs. To achieve this goal molecular and cell biological experiments were designed to incorporate multivalent receptor-ligand interactions. The experiments were performed to create multivalent, artificial, tunable self-assemble signaling hubs to examine their effects in in vitro and in vivo models of hematopoietic lineage commitment. Furthermore, an experimental model was made to create a simple system to examine multivalency at higher resolution. My work primarily consisted of modeling this simple multivalent system.

During my project, I was able to create a framework capable of handling complex multivalent systems. I applied this framework to parameters corresponding to the ongoing biological experiments in the lab. I was able to list the possible states of the trivalent-trivalent interaction using a technique that is applicable to linear molecules with arbitrary valencies. I further established a method to enumerate interactions between multivalent receptors and ligands and to assign rate constants to each interaction. To facilitate this, I made simplifications in case of symmetric molecules and equivalent rate constants. I used a probabilistic approach to calculate the effective concentrations to be used in rate constant calculation in a manner to be applicable to any linear molecule. Then I used computationally constructed differential equation system to calculate the time dependent concentration of the states and used Matlab to solve the equations and visualize the results in an analogous form to the experimental data.

Using the model, I was able to simulate three different experimental setups, and compared the simulation results to the experiments. The first and second model experimental model doesn’t had all the required parameters, and had specific complications, but the third experiment series, which were developed parallel to the simulations, had all the required information. The simulations captured all the known and hypothetical characteristics of the reaction kinetics, and helped understanding the underlying mechanisms and supported the development of the experiments.

As future aims, I envision adaptation of the model for in vivo environments, and developing tools to convert the concentrations of the different states to the propagation of biological signals.


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