Switching proteins on and off

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Switching proteins on and off

Do you remember that first biochemistry exam? Well, with today’s paper we will revisit some of that anxiety!

Allosteric proteins change their structure in response to a trigger, often leading to a change in their activity. Hemoglobin, for example, binds oxygen more easily after the first molecule latches on, making it a classic example of allostery. Today’s paper presents a method to design our own allosteric proteins, custom-built to switch forms based on specific signals.

The team harnessed computational tools to create a module that operates in two states: in the absence of the effector, it remains rod-shaped, but upon binding, it flexes into a V shape. This module is composed of a central “hinge” and two interaction modules, allowing it to connect with other modules and form larger assemblies.

As a first proof-of-concept, the authors built ring-like shapes that could shift between different forms and number of subunits, depending on the hinge’s state. They then synthesized and tested them, proving that they could indeed flip between their two programmed states. More importantly, they showed that the proteins followed the classic allosteric model: either all the binding sites were empty, or they were all occupied, with no in-between.

Expanding on these results, the researchers wanted to mimic the key feature of natural allosteric proteins: the ability to change shape without altering the number of components. They designed proteins with two hinges linked by a short loop and, sure enough, these proteins switched shape as predicted when the effector was added.

Finally, the part of the paper that I found most exciting. The team designed assemblies with six and ten hinge-containing subunits that, in the absence of the effector, formed a stable protein cage. When the effector was introduced, the hinges triggered a conformational change that created tension at the interfaces, weakening the bonds and causing the entire structure to disassemble.

Another standout part of this paper is that most of the tools needed to create these proteins were already available. They used existing tools that predict protein structures with high accuracy, modular switch designs, and algorithms that assemble proteins in stable, functional forms. They simply cleverly combined these tools.

Looking ahead, there are a lot of possible applications I can see:

• Molecular machines: these proteins could be used to create nanomachines capable of transporting molecules or catalyzing a reaction

• Biosensors: The change in conformation after binding can be used to create biosensors that produce, for example, a fluorescent signal

• Drug delivery: Of course, these designed proteins can be used to create drug delivery systems that release their payload only when a specific signal is present, such as a specific pH.

The paper is very cool, and I recommend reading it here!

In other news:

• The DNA origami whisperer: DNA nanotech is great for assembling stuff on the nanoscale, but making larger structures is very challenging. In this paper, the researchers bridge this gap using acoustic fields, controlling the size and the shape of DNA-based materials on a large scale. Maybe you can try yelling at your structures next time and see if it works?

• Spiking DNA neurons: These researchers designed a DNA-based chemical neuron that behaves like a sensory neuron, by responding to cold stimuli with spikes of chemical activity. The team found that this chemical neuron shares mathematical similarities with a model of a biological cold-sensing neuron, following a similar pattern of switching between rest and activity. Crazy stuff. Super cool too.

• A closer look to COVID: If you needed a reminder of 2020, some researchers are still trying to understand how SARS-CoV-2 works. This work uncovers the molecular architecture of the virus’ pore complex with double membrane vesicles, essential for viral replication. This deeper understanding provides new insights for developing new antiviral strategies (fingers crossed).

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