It is natural to ask how the highly crowded environment in the cell interior, where macromolecular concentrations often reach 300 g/L or higher, affects various biomolecular properties, such as structure, dynamics, and diffusion. This question is at the heart of the macromolecular crowding field. One of the most discussed issues is how crowding affects the stability of proteins. Are proteins more, or less, stable inside the cell than what is measured in dilute solutions in the test tube?
The cover image of the July 5 issue of Biophysical Journal shows a model protein immersed in a “soup” of macromolecular crowding particles. The image was created from a snapshot of a computer simulation taken after the protein has folded to its native state. Shown are the main features of the native structure, two α-helices organized as a U-shaped hairpin, at the expense of individual atoms that are not visible. A rainbow color scheme, from blue at the N terminus to red at the C terminus, further helps visualize the structure in a two-dimensional projection.
The image illustrates one of the main computational approaches to crowding, which we also pursue. Rather than attempting to recreate a fully realistic cell interior on the computer, model crowders are used to produce various types of idealized crowding conditions, as exemplified here by the spherical crowders in blue. By varying the interactions between protein and crowders in a controlled way, various crowding effects can be systematically explored.
Our work in this issue focuses on crowders that are perfect, hard spheres and exhibit no attraction to the protein. Such crowders act solely to reduce the space available to the protein chain, which must avoid any part of the crowders due to hard-core steric repulsions. It has long been held that such hard crowders should universally stabilize proteins. We showed, by using a model for folding not previously applied to crowding, that hard crowder particles can, in fact, sometimes destabilize proteins. Our results indicate that destabilization occurs under some conditions, such as low temperatures and crowder concentrations, in combination with certain folding scenarios.
-Saman Bazmi and Stefan Wallin