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Modeling How Molecules Move Inside Cells
Like a thriving town center, the cell is a crowded and busy place where large molecules like proteins continually bump into each other as they hurry toward their destinations.
These molecular interactions are crucial to the proper functioning of the cell because molecules typically work in teams—whether it's assembling to form the cell's supportive scaffolding or transmitting signals from one part of the cell to another like a molecular bucket brigade. By interacting with one another, molecules accomplish the many tasks that keep the cell healthy and able to carry out its unique job in the body.
But for molecules to interact, they first need to encounter one another, a process limited by the diffusion rate—how quickly molecules move through the liquid environment inside cells. Molecules diffuse like people might walk around blindfolded: They bump into structures one another, and they repeatedly change directions. Experiments have shown that molecules move about 15 times more slowly in the cell than in water, but scientists don't fully understand why.
To address this question, systems biologist Jeffrey Skolnick and postdoctoral fellow Tadashi Ando at the Georgia Institute of Technology built a computational model of part of a bacterial cell that contains 15 types of molecules at realistic concentrations.
Using the model, Skolnick simulated how different forces, like crowding or attractions between molecules, affect the diffusion rate. Unlike the real world, where forces can't be turned on or off at will, the computational model let Skolnick examine the effects of each force one at a time.
He found that the crowded environment of the cell only accounts for about 30 percent of the reduced diffusion rate. Molecular shape and molecular attractions also did not substantially affect motion inside cells.
The more dominant effects appear to be the currents and eddies created when molecules slosh through the cell's watery interior. These forces, called hydrodynamic interactions, are similar to the forces exerted by the wake of a speed boat on other nearby boats. And just like on a lake, the hydrodynamic interactions cause the molecules to move in the same direction and at the same speed for a while, even if they don't normally interact with each other. This phenomenon of "correlated motion" could help explain many fundamental biochemical reactions, including those that govern gene regulation and metabolism.
While these findings are interesting in and of themselves, they are just the beginning, says Skolnick. He and his colleagues are currently working on simulating other biochemical processes, including protein folding, formation of the cellular scaffold and breakdown of sugar into cellular energy. Their ultimate goal is to build a complete molecular model of the cell.
With the model, researchers could test how an experimental drug behaves in a virtual cell, or observe how a disease transforms it.
"Of course we are not there yet, but simulations like these represent the first steps toward developing the expertise to explore these kinds of issues," says Skolnick. "They can teach us how to think about how cells work."