The Secret Life of Proteins

Investigating life at the single molecule level

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Did you know that the cells in our bodies house molecules so small that over a billion of them would fit into a grain of sand? These molecules are called proteins and they perform many essential processes inside our cells. Without these proteins, our cells could not function.

Proteins are not just found in our human cells, but in all cells, from bacteria to redwood trees. Some of these proteins are necessary for cell survival, meaning that if you deactivate the protein, the cell will die. This is why one common type of drug, antibiotics, are targeted at the essential proteins in bacterial cells, aiming to kill the bacteria causing an infection.

However, many current drugs lack specificity - meaning the drugs target and deactivate more than one protein. It is difficult to develop drugs that exclusively target only a single protein, but it’s important too because targeting and deactivating multiple proteins can lead to side effects, which range broadly from upset stomachs to strokes.

But, there are scientists working in an innovative field of study called single molecule research, who study the inner-workings of proteins one at a time, so they can figure out how proteins do their jobs. Knowledge about protein mechanisms garnered from single molecule research will help scientists develop new drugs that reach their targets more effectively and treat diseases with fewer harmful side effects.

To understand how this works, think of a protein as a car - most people can give you a basic description of what a car does. It has four wheels and when you press the gas pedal it can move very fast. But the majority of us can’t tell you how a car actually runs. If we popped open the hood we’d be completely mystified by the elaborate mechanisms inside. And if we opened up the hoods of a Subaru and a Tesla we’d find two very different engines, even though they are both cars. However, these engines are understood by trained mechanics, who can use their knowledge to improve and fix our cars.

So, like mechanics, scientists aspire to have a detailed understanding of how different proteins perform their jobs. This is particularly important because scientists are looking for differences between specific proteins from both humans and bacteria. Scientists need to get down to the nitty-gritty parts of the protein and discover what makes it different from all others and understand what makes them unique.

By understanding exactly how a protein acts, scientists can categorize proteins so they have the knowledge to stop that one protein and only that protein. These unique parts help create specific drugs. This is why single molecule research can improve how our current antibiotics and chemotherapeutics work, since it allows for the design of future drugs that work more effectively and with more specificity than the ones currently on the market. 

An example of single molecule research can be found in the Mondragón lab at Northwestern University, which studies many different types of topoisomerases, enzymes that are essential for DNA replication. These molecules help unwind the DNA in cells because if DNA gets tangled and knotted cells will die. However, topoisomerases are not just found in humans, but in all living organisms, including bacteria.  Stopping topoisomerase action with drugs have been used to both kill bacteria and treat cancer. Students in the lab use single molecule microscopy to learn more about how topoisomerases unwind DNA, including figuring out what distinguishes topoisomerases from each other.

In the laboratory scientists can use light microscopes, like the kind found in a high school biology classrooms, to see cells. They can even use sophisticated electron microscopes to magnify 10,000 times more than a light microscope and see individual proteins that have been frozen in place. But taking a look at something as tiny as a single protein while it moves requires very specialized techniques. Scientists are unable to see the movement of individual proteins using conventional microscopes, so they utilize unique single molecule methods.

One such method is Force Microscopy, which detects the effects of a protein, even though the protein itself cannot be seen. For example, scientists may not be able to see a piece of DNA or a protein, but they can attach a giant bead (which they can easily see) to a piece of DNA and watch as the length of the DNA changes or as a protein begins pulling on the DNA.

It’s similar in principal to how a fisherman can tell she’s caught a fish. The fish exerts a force on her fishing rod, which causes the rod to bend. Though the fisherman can’t see the fish, she knows she has it on the hook because of the movement of the rod.  Similarly, when a protein pulls on DNA, scientists can see the attached bead move. So, they know the protein is there even if they can’t see it. 

Single molecule research has opened a new window into the molecular world, but it is still a relatively new area of investigation, with many new techniques still being established. Once a protein’s specific function and unique properties have been identified, that information can be passed on to chemists and computer scientists who figure out how to use the information, for example, to design better drugs. In this way, single molecule research provides a crucial part of the information needed to one day bring better, more effective drugs to the market.

Over the past 20 years single molecule techniques have opened up a window into the world of protein movement. Studies at this single molecule level are expanding to encompass an ever growing range of proteins and incorporating new techniques as they are developed. While we may not know where this new information will ultimately lead, it is clear that there are many things we don’t yet understand about proteins. That is why scientists here at Northwestern and all over the world are dedicated to investigating these proteins and continuing the search for answers.

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