A Modular Framework for Computer Models of Bacterial Cells

Jordan Atlas, Cornell University

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 is the development of 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 use the sensitivity analysis of the original 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 project proposed here includes two main parts: 1) Development of novel algorithms that facilitate rapid addition of chemically detailed modules to the hybrid cell models, and 2) Utilization of a statistical mechanics method for parameter estimation that takes advantage of high-performance computation.

In particular, I am working on the Minimal Cell Model (MCM) with Dr. Michael Shuler. A “minimal cell” is defined as a prokaryote with the minimum number of genes for growth and replication in an environment with ample nutritional resources. The overall goal of my research is to complete a genomically-detailed MCM that addresses all the metabolic and non-metabolic features of a chemoheterotrophic bacterial cell. We use as our basis the Cornell coarse-grained E. coli model (Domach et al. Biotech. and Bioeng. 67, 827-840), comprised of 36 ODEs, two algebraic equations, and 31 discrete events. In our approach, computational challenges immediately arise 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 can be used in the sensitivity analysis of the model. Stability analysis reveals 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. Thus, moderate-sized hybrid cellular models provide a systematic way to relate genomic detail to physiologic response with a broad applicability in fundamental and applied research.

Abstract Author(s): Jordan C. Atlas, Evgeni V. Nikolaev, and Michael L. Shuler