Team successfully simulated glucose metabolism in the cell.

Researchers have built a computer model of an E. coli cell. In a test of its response to sugar in its environment, the in silico model accurately simulated the behavior of living cells, they report.

The work is a result of a collaboration between experimental scientists at the Max Planck Institute of Biology and theoretical scientists at the University of Illinois. Their study appears in PLoS Computational Biology in a paper titled “Noise Contributions in an Inducible Genetic Switch: A Whole-Cell Simulation Study.”

“This is the first time that we’re modeling entire cells with the complete contents of the cellular cytoplasm represented,” says Illinois postdoctoral researcher and lead author Elijah Roberts, Ph.D. “We’re looking at the influence of the whole cellular architecture instead of modeling just a portion of the cell, as people have done previously.”

Other researchers have begun studying the effects of molecular crowding on cellular processes but not at the scale of an entire cell. Those studying live cells can discover variations in the copy number of a particular protein in a population of cells. But they are less able to observe the microscopic details that give rise to such differences between genetically identical cells.

Well-designed computer simulations of whole cells can track every reaction within the cells while also accounting for the influence of molecular crowding and other variations between cells, Dr. Luthey-Schulten points out. For example, by running simulations on models of two E. coli strains, the researchers were able to see that bacterial cell architecture does indeed affect the reactions that occur within the cells.

When sugar was present in its environment, a longer, narrower E. coli strain was able to ramp up production of a sugar-transporter protein much more quickly than a bigger strain, the researchers found. That difference had a lot to do with the distribution of molecules in each cell type, Roberts said.

The computer simulation also showed how molecular crowding influences the behavior of a molecule that, when it binds to DNA, shuts down production of the sugar-transporter protein. Even when it wasn’t bound to DNA, this repressor remained close to the binding site because other molecules in the cell blocked its escape. These intracellular obstacles reduced its ability to diffuse away.

The new model is only a first step toward an accurate simulation of a whole working cell, the scientists assert. Development of better models will rely on research on actual cells. Such data provides the framework for improving computer models and offers a real-world test of the in silico cells’ ability to recreate the behavior of living cells, said University of Illinois chemistry professor Zaida Luthey-Schulten, Ph.D., who led the research. Future studies by Dr. Luthey-Schulten’s team will develop the E. coli models and will focus on methane-generating archaeal microbes.

Dr. Luthey-Schulten had done molecular dynamics simulations of individual molecules or groups of molecules involved in information processing. Then in 2006 she saw a paper by Wolfgang Baumeister, Ph.D, and his colleagues at Max Planck that located every one of a bacterium’s ribosomes inside the cell. Dr. Luthey-Schulten asked Dr. Baumeister’s team if they would repeat the study in E. coli.

Once the new ribosome data were available, Dr. Roberts looked to other studies that described the size distribution of the rest of the molecules that take up space in the cell. By adding these to the ribosome data, he developed a 3-D model that showed the degree of molecular crowding in a typical E. coli cell.

Dr. Luthey-Schulten was amazed at how little space remained inside the cell, she said. “I think, like everybody else, my perception of the cell up until Wolfgang and Julio’s 2006 article had always been that it’s a pretty big sack of water where a lot of chemical reactions occur. But in fact there are a lot of obstacles in the cell, and that is going to affect how individual molecules move around, and it’s going to affect the reactions that occur.”

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