Shape matters in macromolecular crowding

Abstract

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,