The depletion attraction: an underappreciated force driving cellular organization

Abstract

Cellular structures are shaped by hydrogen and ionic bonds, plus van der Waals and hydrophobic forces. In cells crowded with macromolecules, a little-known and distinct force-the "depletion attraction"-also acts. We review evidence that this force assists in the assembly of a wide range of cellular structures, ranging from the cytoskeleton to chromatin loops and whole chromosomes.

Figure 1.

The depletion attraction and its role in cellular organization. (A) Many small spheres (purple) representing soluble macromolecules bombard three large spheres (red), representing cellular complexes, from all sides (arrows). When two large spheres come into contact (right), the small ones exert a force equivalent to their osmotic pressure on opposite sides of the two large ones to keep them together. (B) The shaded regions in this alternative view show regions inaccessible to the centers of mass of the small spheres. When one large sphere contacts another, their excluded volumes overlap to increase the volume available to the small spheres (increasing their entropy); then aggregation of the large spheres paradoxically increases the entropy of the system. An analogous effect is found when a large sphere contacts the wall.

Figure 2.

Examples of AO theory. Overlap volumes are green; small spheres not depicted. (A) Interactions within and between proteins. (i and ii) The attraction increases as the overlap volume increases; larger spheres generate larger overlap volumes and so are more likely to aggregate. (brackets) Adding one large sphere to two large spheres cooperatively generates two (not one) extra overlap volumes. (iii) Aligning two rods (in the same or different proteins) generates a large overlap volume (and thus attraction). (iv) Folding a tube into a helix generates an overlap volume that stabilizes the helix. (B) Interactions involving chromatin. (i) When large spheres (polymerizing complexes and clusters of bound transcription factors) are threaded on a string (DNA or chromatin fiber) the attraction is countered by the entropic cost of looping. (ii) Beads (nucleosomes and heterochromatic clumps) on one string can collapse onto each other (to pack a chromatin fiber or mitotic chromosome). (iii). Similar strings of beads (factories and heterochromatic clumps) can align perfectly, whereas dissimilar ones cannot. (iv) Large beads (NORs and centromeric heterochromatin) on different strings can aggregate (into nucleoli, chromocenters). (C) Confined spaces. Enclosing a sphere in a confined space (a pore or a proteasome) generates a large overlap volume (and thus attraction).