Model and computational simulation of yeast gradient sensing. (A) Proposed four-phase model of yeast gradient sensing. In vegetative cells, the receptor and G protein are uniformly distributed on the PM. After their global internalization, the GTM is assembled at the DS. Tracking begins when a gradient of activated receptor on the cell surface induces a separation of exocytosis and endocytosis, which results in GTM redistribution upgradient (green triangle) by a treadmill-like mechanism. The GTM stops tracking at the CS and centers around the future shmoo/fusion site during the stabilization phase. The blowups show the molecular mechanisms of DS assembly (i) and biased secretion during tracking (ii). (B) Network diagram of the computational model. (i) Three dimeric forms of the receptor are explicitly modeled: II, IA, and AA. (ii) The network symbols are as follows: pheromone (L, ligand); heterotrimeric G protein (G); Gα-GTP (Ga); Gα-GDP (Gd); free Gβγ and its phosphorylated form (Gbg and GbgP); the Yck1/2 receptor kinases (Yck); and the inactive and active MAPK (Fus3 and Fus3a). The green bar represents internalization of the heterotrimeric G protein with II and IA. (C–E) Selected outputs from modeling simulations. The x-axis of each plot corresponds to the cell circumference. Vertical black lines indicate the peak values of each parameter at each time point. The green panel (top) shows the applied pheromone gradient. The dashed green and red boxes indicate the start and end of tracking, respectively. (C) Outputs from the standard model. The i-IA⋅G parameter is the internalization rate of the IA-receptor dimer bound to one heterotrimeric G protein. (D–F) In silico experiments. Outputs from modified models in which the receptor is uniformly distributed at the start of the simulation (D); Gβγ is uniformly distributed at the start of the simulation (E); and receptors are monomeric and cointernalization of the receptor and G protein cannot be induced by pheromone (F).