Psychologists have long known that people act differently in a crowd: You’re more likely to be socially withdrawn, and less likely to perform well on complex tasks. But the behavior-altering effects of crowded conditions aren’t limited to people, or even to social animals – biochemical reactions are also drastically different in tight spaces, a physical and chemical reality that has significant consequences.
When biologists study reactions, they like to follow the age-old dogma of the scientific method: isolate the variable you’re studying. If you want to know how various concentrations of a protein interact with an antibiotic, you’re probably going to toss different amounts of the two players into several test tubes and see what happens. This reductive approach is doubly attractive: It’s convenient when interpreting results (a simpler system presents fewer confounding variables), and it's a lot more convenient to work with.
But there is a trade-off. By adopting a more simplistic experimental framework, these tests may be neglecting one critical aspect of biological systems: the crowdedness of the cell. Trading a living cell for the spaciousness of a laboratory test tube can be as stark a transition as leaving a Manhattan loft for a wide-open Nevada ranch (in terms of population density).
One obvious result of a crowded milieu of intracellular soup is less available space for each molecule, which increases the effective concentration, or chemical potential. By cramming more molecules together, you’re improving the chances that two reactants will link up. It’s an exponential relationship: toss in a few more reactants, and the chemical potential responds dramatically.
Another effect of molecular crowding is a slowdown of molecular diffusion, particularly for large molecules. Imagine moving through a toy store, propelled by an unwavering need to snap up the last Furby stuffed animal for your kid’s upcoming birthday. The task is harder amid the throngs of Black Friday shoppers, but even with such crowds, your child (i.e., a small molecule) will be better able to slip between the over-zealous consumers. Lower rates of diffusion mean that diffusion-limited reactions will happen slower, especially those involving larger constituents.
These two consequences of molecular crowding – higher chemical potentials and lower diffusion rates – counteract each other when it comes to intermolecular reactions, making the change in reaction rate difficult to predict. Usually, however, there is a sweet spot where reaction rates are optimized, with enough coziness to encourage reactivity but not too much to gum up the works. Determining how this optimum relates to various biochemical reactions is a fascinating biological and evolutionary question. Do cells shift their internal contents to favor certain reactions at particular times? How have the molecular sizes of toxins shifted over evolutionary time, and could this be a response to increasingly complicated – and crowded – target cells?
These are far-reaching issues that will require extensive work, but for now, Dr. R. John Ellis is urging the research community to at least take molecular crowding into account when performing experiments. The effects on thermodynamics and kinetics are so large,” he cautions in a 2001 paper, “that it can be stated with some confidence that many estimates of reaction rates and equilibria made with uncrowded solutions in the test tube differ by orders of magnitude from those of the same reactions operating under crowded conditions within cells.”
We would never draw conclusions about modern human civilization based solely on a ranching community in rural Nevada; it’s time we study biochemical reactions in their native habitats.
