Governing Principles of Multiprotein Complex Formation on the Cell Membranes: An Investigation using Single-Molecule Resolution Spatio-Temporal Stochastic Computer Simulations and Analytical Calculations

Abstract

A significant number of the cellular protein interaction networks, such as receptor mediated signaling and vesicle trafficking pathways, includes reactions that involve membranes as a molecular assembly platform. Multiprotein membrane complex formation is an intricate interplay between the particular reaction network, cell size and shape, binding affinities of the proteins and lipid molecules and their concentrations. Mathematical models along with computer simulations provide insight into the dynamics of complex formation and help identify general principles that govern successful recruitment and assembly on membranes. However, sufficiently long and physically accurate simulations of protein assemblies are quite challenging. In this work, using a very efficient in-lab developed software, we have performed single-molecule scale stochastic simulations of protein interactions on the membranes. In addition, for simple reaction networks, assuming spatially well-mixed systems of fixed volume, approximate analytical formulas of equilibrium concentrations of membrane multiprotein complexes were derived as functions of system parameters such as reaction rates and cell geometry. Using these formulas, we have identified modes of membrane recruitment for protein assemblies that depend on molecular interaction affinities. Overall, our results suggest that proteins might have evolved into diverse reaction network structures to fine-tune the time to complete the assembly of membrane protein complexes in desired quantities. We discuss possible consequences of our findings on an elementary clathrin-dependent endocytic network as a case study.