(237a) In Silico Bacterial Cells: from Generalized Coarse-Grained to Genome-Specific Modular Models

We propose a dynamic modeling framework to integrate genomic detail and cellular physiology within functionally complete ‘hybrid' bacterial cell models. An initial step in this approach was to develop a whole-cell coarse-grained model which explicitly links DNA replication, metabolism, and cell geometry with the external environment. A hybrid model can then be constructed from chemically-detailed and genome-specific subsystems, called modules, inserted into the original coarse-grained model. We used sensitivity analysis of the coarse-grained model to identify which pseudo-molecular processes should be de-lumped into molecularly-detailed mathematical modules to implement a particular biological function. The main goals of this project are: 1) To develop of novel algorithms that facilitate rapid addition of chemically detailed modules to the hybrid cell models, and 2) To estimate model parameters using a statistical mechanics method for parameter estimation that takes advantage of high-performance computation.

To demonstrate our approach, we will describe our Minimal Cell Model (MCM), which is currently under development. We define a “minimal cell” as a prokaryote with the minimum number of genes for growth and replication in an environment with ample nutritional resources. The overall goal of this project is to complete a genomically-detailed MCM that addresses all the metabolic and non-metabolic features of a chemoheterotrophic bacterial cell. We used as our basis the Cornell coarse-grained E.coli model, comprised of 36 ODEs, two algebraic equations, and 31 discrete events. In our approach, computational challenges immediately arose due to discrete events (e.g. cell division, etc.), resulting in non-continuous periodic solutions. However, the return map corresponding to the cell division cycle is smooth and, hence, the map was used for sensitivity analysis of the model. Stability analysis revealed the potential for autonomous quasi-periodic oscillations with ‘periods' of 20-30 hours corresponding to the Hopf bifurcation of the cell-division return map. Given the primary cell division cycle of 45 minutes, the secondary long-term ‘oscillator' has to be transmitted to the progeny cells. Further studies are needed to characterize the parameters relevant to these intriguing oscillations with periods much longer than the cell cycle.