Watching Proteins Dance

When proteins that should be moving start to aggregate in immobile clumps this can lead to disease. What happens to disrupt the dance? Researchers from  Ecole Polytechnique Fédérale de Lausanne (EPFL) have created a model which captures the dynamic behavior of intrinsically disordered proteins and starts to answer this question.

Models of two proteins. The one on the left aggregates and starts to lose it’s flexibility. The aggregate is about 50 nanometers across.

Some proteins fold precisely to form specific shapes, such as helices and sheets, but in others most of the structure is disordered. These intrinsically disordered molecules control a myriad of functions within all kinds of living cells. They associate briefly in concentrated droplets (condensates) and then they dissipate again. But sometimes they aggregate into a solid mass loosing their flexibility. This irreversible aggregation has been linked to diseases like Alzheimer’s, Parkinson’s, Huntington’s and amyotrophic lateral sclerosis (Lou Gehrig’s disease).  

Snapshots of an intrinsically disordered protein show that it has no preferred shape.
Snapshots of an intrinsically disordered protein obtained using NMR spectroscopy. In this thylakoid soluble phosphoprotein, found in spinach, a small section always organizes itself as a helix, but the remainder of the protein is disordered. Each time we look (shown as different colored structures, overlaid in this image) we see a different shape. Structures from the Protein Data Bank.

Modelling the dance

It is exceedingly difficult to see what protein molecules are doing inside our bodies, and so we create models. If a model can capture enough of the physics (and the chemistry) and behaves like proteins in a cell we can use it to test ideas about aggregation.

Julian Shillcock and his coworkers at EPFL have created a model that does this. They represent the long protein molecules as chains of soft beads, some of which are sticky. The sticky beads represent chemical structures in the protein that can form associations. Computer simulations using this model reveal how these sticky regions create structure within and between the chains. We can watch the progression of the dance rather than just looking at snapshots.

Chains of beads - like short bead necklaces - represent long intrinsically disordered protein chains
Models of proteins, each soft bead represents a section of the protein. The chemistry is captured in the interactions between the beads, the yellow beads represent sections of the protein that attract each other (tend to stickiness)

Stickiness matters

We can think of these intrinsically disordered proteins as spaghetti, well cooked and in the pan of water just before you serve it. The way that the strands stick as they touch determines the fluidity of the system. Too much stickiness and the spaghetti becomes an inedible mass (you probably cooked it for too long).

The chef looks at spaghetti that is cooking on the stove. Has it overcooked? This is thought model for the behavior of intrinsically disordered proteins in the body.
Cooking Spaghetti

The researchers simulated the behavior of proteins implicated in amyotrophic lateral sclerosis. They discovered that the distribution of the sticky regions is critical. Some locations cause more trouble than others and the behavior of the chain ends (the red beads) is critical.

For example, in the video at the start of this blog post we see the predicted behavior of proteins that are have different distribution of sticky regions. In the system on the left the sticky regions are closer together than those in the system on the right. The proteins in the system on the right remain intrinsically disordered. The proteins in the system on the left bunch together and become less flexible. This could be the start of disease.

Each simulation (3 million steps) took 20 days on a 4.5 GHz Ryzen Threadripper 3970X computer.

This work could help to target drugs to prevent the irreversible aggregation of the flexible proteins. The simulations provide new insights into the dance of life.

Learn more

Read the new paper: Model biomolecular condensates have heterogeneous structure quantitatively dependent on the interaction profile of their constituent macromolecules, by Julian C. Shillcock, Clément Lagisquet, Jérémy Alexandre, Laurent Vuillon and John H. Ipsen.

Learn more about protein condensates: A Newfound Source of Cellular Order in the Chemistry of Life, published by Viviane Callier in QuantaMagazine in2021.

Read an open-access review on “Intrinsically Disordered Proteins and Their “Mysterious” (Meta)Physics” published by Vladimir N. Uversky in Frontiers in Physics in 2019.

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