Solving the puzzle of self-assembly

Mathematical modeling reveals some of the fundamental constraints that affect how biological structures self-assemble from building blocks.
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A model showing different building blocks self-assembling into a ring. Image credit: Philipp M. Geiger (CC BY 4.0)

The self-assembly of a large biological molecule from small building blocks is like finishing a puzzle of magnetic pieces by shaking the box. Even though each piece of the puzzle is attracted to its correct neighbours, the limited control makes it very hard to finish the puzzle in a short amount of time.

The problem becomes even more difficult if several copies of the same puzzle are assembled in one box. If several puzzles start at the same time, the different parts might steal pieces from each other, making it impossible to successfully complete any of the puzzles. This is called a depletion trap. If the box is only shaken and there is no real control over individual pieces, these traps occur at random.

Overcoming these random depletion traps is an important challenge when assembling nanostructures and other artificial molecules designed by humans without wasting many, potentially expensive, components. Previous studies have shown that when multiple copies of the same structure are assembled simultaneously, slowing the rate of initiation increases the yield of correctly-made structures. This prevents new structures from stealing pieces from existing structures before they are fully completed.

Now, Gartner, Graf, Wilke et al. have used a mathematical model to show that changing the way initiation is delayed leads to different yields. This was especially true for small systems where fluctuations in the availability of the different pieces strongly enhanced the initiation of new structures. In these cases, the self-assembly process terminated undesirably with many incomplete structures.

Nanostructures have various applications ranging from drug delivery to robotics. These findings suggest that in order to efficiently assemble biological molecules, the concentrations of the different building blocks need to be tightly controlled. A question for further research is to investigate strategies that reduce fluctuations in the availability of the building blocks to develop more efficient assembly protocols.