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Protein Folding

Shape matters in macromolecular crowding

Compact forms are stabilized more than larger forms

by Celia Henry Arnaud
October 13, 2018 | A version of this story appeared in Volume 96, Issue 41


Surface potential images of domain-swapped and side-by-side dimers of GB1.
Credit: Proc. Natl. Acad. Sci. USA
The domain-swapped dimer of GB1 (left), which forms an elliptical structure, is more compact than the side-by-side dimer, which forms a "kissing spheres" structure. Electrostatic surface potentials are shown in red (negative) and blue (positive).

In the crowded conditions typical of biological cells, nonspecific interactions can affect macromolecules’ behavior. In theoretical studies of crowding, macromolecules are often treated as sterically repulsive hard spheres, with no consideration of the actual shape of the molecules. Researchers have long hypothesized that the effects of this type of repulsion depend on a protein’s shape, but they haven’t been able to test that hypothesis. Now, Gary J. Pielak and coworkers at the University of North Carolina, Chapel Hill, have used dimers of a protein domain called GB1 to show that molecular shape does indeed matter in crowding effects (Proc. Natl. Acad. Sci. USA 2018, DOI: 10.1073/pnas.1810054115). Mutations within GB1 lead to dimers that have similar surfaces but different shapes. A single mutation in the natural protein results in a side-by-side dimer, with a shape that Pielak describes as two “kissing spheres.” Three additional mutations result in the so-called domain-swapped dimer, which is flattened and more elliptical than the other dimer. Pielak and coworkers label the proteins with 5-fluorotryptophan and use 19F NMR to determine how crowded conditions affect the dimers. As predicted, they find that the more compact domain-swapped dimer is more stabilized by crowding than is the side-by-side dimer. The results verify that shape does indeed control the effects of crowding and that more compact forms are more likely to be stabilized in the crowded cellular environment.


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