The mystery of protein folding

It has been recognized for many years that proteins have a particular way of being folded. In fact, many proteins will refold spontaneously if they become unfolded. This folding was recognized by Linus Pauling in the 1960s. (Pauling eventually won the Nobel Prize for is work on DNA.)

It was not until later, however, that we began to understand that the particular way in which a protein is folded is very important to its function. That shape of a protein is what allows it to do its job in and around the cell.

As time has gone on, we have also discovered that some proteins cannot spontaneously refold and actually need help to get into their proper folding configuration. There are some special RNA molecules whose job it is to ensure that these proteins are folded properly.

There has also been a realization recently that the folding of proteins actually may hold the key to understanding and combating some diseases such as Alzheimer’s. And so has launched the protein folding phenomenon in the biomedical community. There is even a game called Foldit which has challenged humans to figure out the proper steps in folding proteins (this game is legitimately for research purposes), a job that computers have not been great at.

The problem with trying to understand protein folding is that there are so many possible steps in the folding process that it has been unfeasible to explore all of those possibilities, even with the computing power we have now.

This means we have had to try to tackle this problem with other means. One possible way is understanding the intermediate states in the folding process (which is something a game like Foldit can help with), but doing this experimentally has been a challenge as developing a machine that has all of the right characteristics for studying this process experimentally has been difficult.

Recently the idea has been to repurpose a machine that has been used for other tasks, but even that has been a challenge. The atomic force microscope is a tool that has been used to determine the structure of materials at very small levels by using a small metal piece (a cantilever) that has a very sharp edge underneath it. When bouncing a laser beam off of the cantilever, it causes it to bend, and how far it bends is based on how close the tip is to the material. By running this along the surface of the material, you can determine the shape of the material.

The idea for repurposing this tool has been that they can attach the sharp portion of the cantilever to a protein and let the cantilever pull on the protein gently and cause it to unfold. The problem that researchers have run into is that the machine, as currently built, does not work well in water, which is precisely the environment proteins need to be in.

To get around this, a research group has modified the typical design of an atomic force microscope. After working on these modifications, they used their “new” tool to study protein folding, and it is already yielding results. They discovered that in a certain protein of interest that there where previously unknown intermediate states in the folding process.

This new tool may help us to understand better the protein folding mechanism and allow us to develop better drugs with this knowledge. Hopefully, protein folding will not remain a mystery.

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