- 12:00 PM

Coarse-Grained Kinetic Monte Carlo Models: Applications to Membrane Receptor Dimerization

Stuart D. Collins, Chemical Engineering, University of Delaware, 150 Academy St, Newark, DE 19716, Abhijit Chatterjee, Theoretical Division, Los Alamos National Laboratory, T-12 MS B268, Los Alamos, NM 87545, and Dion Vlachos, Director of Center for Catalytic Science and Technology (CCST), University of Delaware, Newark, DE 19716.

The ErbB family of receptors is dysregulated in a number of cancers, and the signaling pathway of this receptor family is a critical target for several anti-cancer drugs. Therefore, a detailed understanding of the mechanisms of receptors activation is critical. However, despite a plethora of biochemical studies and single particle tracking experiments, the early molecular mechanisms involving epidermal growth factor (EGF) binding and EGF receptor (EGFR) dimerization are not as well understood. Due to the large disparity of time and length scales involved in receptor dimerization reactions, we adapt the coarse-grained Monte Carlo (CGMC) simulation framework to enable the simulation of in vivo receptor diffusion and dimerization.

On-lattice kinetic Monte Carlo (KMC) simulations have extensively been applied to numerous systems. However, their applicability is severely limited to relatively short time and length scales. Recently, the CGMC method was introduced to greatly expand the reach of the lattice KMC technique. Herein, we extend the previous spatial CGMC methods to multicomponent species and/or site types. Numerical examples are presented to demonstrate the method. Furthermore, we introduce the concept of homogenization at the stochastic level over all site types of a spatially coarse grained cell. Homogenization provides a novel coarsening of the number of processes, an important aspect for complex problems plagued by numerous microscopic processes (combinatorial complexity). As expected, the homogenized CGMC method outperforms the traditional KMC method on computational cost while retaining good accuracy.

Using the CGMC method, spatial modeling of ligand-mediated membrane receptor dimerization reaction dynamics was peformed. Furthermore, the simulations demonstrate the importance of spatial heterogeneity in membrane receptor localization. Mathematical models, especially one that takes into account spatial heterogeneity, show mechanistic understanding of receptor activation that may in turn enable improved future cancer treatments.