MIL Cell: A tool for multi-scale simulation of yeast replication and prion transmission.

Abstract

AbstractThe single celled bakers yeast, Saccharomyces cerevisiae, can sustain a number of amyloid-based prions, with the three most prominent examples being [URE3] formed from the Ure2 protein (a regulator of nitrogen catabolism), [PSI+] formed from the Sup35 protein (a yeast translation termination release factor) and [PIN+] formed from the Rnq1 protein (of as yet unknown function). In a laboratory environment, haploid S. cerevisiae cells of a single mating type can acquire an amyloid prion in one of two ways (i.) Spontaneous nucleation of the prion within the yeast cell, and (ii.) Receipt via mother-to-daughter transmission during the cell division cycle. Similarly, prions can be lost from a yeast due to (i) Dissolution of the prion amyloid by its breakage into non-amyloid monomeric units, or (ii) Preferential donation/retention of prions between the mother and daughter during cell division. Here we present a computational tool, called MIL-CELL, for modelling these four general processes using a multiscale approach that is able to describe both spatial and kinetic aspects of the yeast life cycle and the amyloid- prion behavior. The yeast growth cycle is considered in two stages, a mature yeast that is competent to bud (M), and a daughter yeast (D) defined as a fully grown and detached bud. In the virtual plate experiment each transition in yeast growth is stochastically regulated, according to temporal and spatial characteristics, in a manner able to incorporate concepts of confluent growth. Between the relatively coarse time-points used for the particle level description, a set of differential equations, describing the nucleation, growth, fragmentation and clumping of amyloid fibrils, is solved numerically, for each individual yeast cell. Distribution of amyloid between the mother and the daughter is carried out by solving a set of kinetic partition equations between mother and the newly forming (and still attached) daughter during the yeast budding stage. In this paper we describe the workings of the model, the assumptions upon which it is based and some interesting simulation results that pertain to wave-like spread of the epigenetic prion elements through the yeast population. MIL-CELL (Monitoring Induction and Loss of prions in Cells) is provided as a stand-alone graphical user interface-based executable program for free download with the paper (supplementary section). MIL-CELL download: https://drive.google.com/drive/folders/1xNBSL_2sGNkyXfYLYUyXjyM9ibGAcQUL?usp=sharing