Date of Completion

12-13-2017

Embargo Period

12-12-2022

Keywords

Ligand Receptor Dissociation, Multiphysics Simulation, Virtual Reality, Collective Cell Migration, Stochastic Modeling, Anomalous Diffusion, Membrane Fluctuation, Receptor Diffusion, Membrane Diffusion, Coarse-grain Molecular Dynamics Simulation, Chemotaxis

Major Advisor

George Lykotrafitis

Associate Advisor

Horea Ilies

Associate Advisor

David M. Pierce

Associate Advisor

Ying Li

Associate Advisor

Julian Norato

Field of Study

Mechanical Engineering

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Modeling multiple receptor-ligand interactions, where receptors are distributed on a fluctuating membrane, is challenging since it involves two very distinct timescales. We overcame this obstacle by introducing an essentially time coarse-graining algorithm by employing a stochastic methodology to compute the probability of the bond remaining intact at specific time step. We developed a computational framework to model the complex receptor and ligand interaction by using a survival probability function. Using the model, we studied how membrane oscillations are affected by adhesion between substrate ligands and membrane receptors, and how diffusion of membrane receptors depends on ligand-receptor adhesion.

In order to simulation complex receptor-ligand interaction, we developed a high-performance computing (HPC) computational framework to program complex independent processes individually and modularly. IMPETUS – Interactive MultiPhysics EnvironmenT for Unified Simulations, is an object-oriented, easy-to-use, high performance, C++ program developed for three-dimensional simulations of complex physical systems. The program uses Message Passing Interface (MPI) for parallel computing operations and utilizes contemporary object-oriented programming techniques to provide an interactive and easily customizable coding environment for users to develop complex multi-physics simulations. A critical factor to correctly implement simulations and interpret the data is the interaction between computer and user. Intuition, conjecture, and experimentation are essential driving forces behind innovation and scientific discovery. To augment these principles, we have developed a virtual reality environment for interactive multiphysics simulation and data visualization. This was made possible by integrating IMPETUS with the Unreal Engine 4 and consequently named IMPETUS-VR. Users can create, visualize, and interact with their simulations or with three-dimensional images using IMPETUS libraries.

From the IMPETUS simulations, we observed that the ligand-receptor adhesion restricts the modal shapes of a membrane. Adhesion not only affect the morphology of the membrane but also the diffusion of the corresponding receptors. Anomalous sub diffusion was observed when a finite hierarchy of ligand trap distribution on the substrate was introduced. We observed that as the ligand density increases, anomalous diffusion exponents become smaller and the overall diffusion decreases. The simulation results demonstrated that our computational framework could be used to model adhesion of lipid membrane.

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