University of North Carolina
Title: How first passage time problems can help us understand transport of biomolecules in crowded environments.
My talk will explore how first passage time problems are used to model molecular transport in biology. cellular environments are typically crowded and highly heterogeneous. Even if large molecular species are not directly involved in a given reaction, they can influence it through steric interactions. By modeling the random motion of individual molecules in heterogeneous environments, first passage time statistics can be used to understand the dynamics of complex physiological processes. I will discuss two examples
(i) First, I will show how antibodies are dynamically tuned to anchor large nanoparticles, such as viruses, to constitutive elements of a mucin polymer gel. Mucus is a vital component of our immune system and provides a first line of defense against infection. Large nanoparticles such as bacteria are trapped within the tangled polymer network, preventing contact with the mucus membrane and subsequent infection. However, some nanoparticles, such as certain viruses, are small enough that they can freely diffuse through the polymer matrix. One hypothesis for how smaller nanoparticles could be trapped is that they are crosslinked to the mucin network by antibodies. Indeed, antibodies are present in large quantities within mucus. However, the hypothesis was previously discounted because antibodies typically have very weak affinity for mucin. Counter to the prevailing theory that antibodies are only effective if they have strong affinity to mucin, I will show how weak affinity and rapid binding kinetics substantially improves their ability to trap large nanoparticles.
(ii) In the second half of my talk I will present theoretical support for a hypothesis about cell-cell contact, which plays a critical role in immune function. A fundamental question for all cell-cell interfaces is how receptors and ligands come into contact, despite being separated by large molecules, the extracellular fluid, and other structures in the glycocalyx. The cell membrane is a crowded domain filled with large glycoproteins that impair interactions between smaller pairs of molecules, such as the T cell receptor and its ligand, which is a key step in immunological information processing and decision-making. A first passage time problem allows us to gauge whether a reaction zone can be cleared of large molecules through passive diffusion on biologically relevant timescales. I combine numerical and asymptotic approaches to obtain a complete picture of the first passage time, which shows that passive diffusion alone would take far too long to account for experimentally observed cell-cell contact formation times. The result suggests that cell-cell contact formation may involve previously unknown active mechanical processes.