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Water Solves Protein Folding Problem

The way water interacts with proteins explains one of the great mysteries of protein folding

One of the grand challenges in molecular biology is to understand how proteins fold into complex 3D shapes.

Proteins are chains of amino acids made by various molecular machines inside cells. When proteins first form, they are random coils. In this state, they are at best benign and at worst toxic–the prions that cause problems such as mad cow disease are misshapen proteins.

But soon after this, a small miracle occurs. These huge molecular chains quickly self-assemble into the complex 3D shapes that allow them to perform their jobs within the cellular machinery.

This performance is so astounding, it’s worth dwelling on.

When two amino acid bond, they can take on one of roughly ten different orientations to one another. So a chain of 3 amino acids can be 10^3 different shapes.

The fastest folding protein discovered so far is a structure called a 3-stranded beta sheet. As it’s name suggests, it is a surface formed from three strands of protein that bind together. In total, these sheets contain up to 90 amino acids and so in theory can take on any of 10^90 different shapes.

If these shapes were tried at the rate of 100 billion a second, it would take longer than the age of the Universe to find the correct fold. And yet the 3-stranded beta sheet forms in just 140 nanoseconds.

It would less surprising to leave a few lumps of metal and plastic in the back yard and discover the next morning that it had self-assembled into a laptop computer.

There are various suggestions for how protein folding does its magic. One of the most promising is the idea that evolution has selected only those proteins that collapse naturally into the required shape. To do this, the energy of the final shape has to be lower than the starting energy and all the steps in between.

That means the energy landscape of this system must be funnel-shaped. By this way of thinking, protein folding works because, in exploring the space of possible shapes, the structure “falls” through this funnel.

But there is a problem. If this were the whole story, proteins ought to be more stable at lower temperatures. But they’re not. A well know property of many proteins is that their structure collapses as the temperature drops. So any model of protein folding has to account for this too.

Today, Olivier Collet at Nancy University in France has worked out what’s going on and the key, he says, is water.

He points out that protein folding does not occur in isolation but in solution. So the amino acid chain is surrounded by water molecules. At close range, these form a shell around the protein chain. What Collet has done is study the behaviour of the water molecules in this first shell.

Collet says that the water molecules form hydrogen bonds with the amino acids. As long as the temperature remains relatively high, the hydrogen bonds are constantly being broken and forming again and the folding proceeds in the usually rapid fashion.

But if the temperature drops, the hydrogen bonds become permanent, allowing the protein to take on new low-energy configurations. This dramatically changes the energy landscape, creating additional valleys that correspond to these new low-energy shapes. So instead of falling through the energy funnel, the protein becomes stuck in another valley that corresponds to an incorrect shape.

That’s a useful idea. It neatly explains the temperature problem within the existing theory.

It also suggests that a powerful new understanding of protein folding could come from a better understanding of the properties of water at these tiny scales.

As we saw last week, the network of links between water molecules confined on this scale have a dramatic impact on its behaviour. There may even by a quantum coherence associated with these links, which immediately suggests a new way to approach this problem–treating it as a kind of quantum computation.

That could open a whole new avenue of work and we’ll be watching. Fascinating stuff!

Ref: How Does The First Water Shell Fold Proteins So Fast?

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