The "protein folding problem" consists of three closely related puzzles: (a) What is the folding code? (b) What is the folding mechanism? (c) Can we predict the native structure of a protein from its amino acid sequence? Annual Review of Biophysics, Vol 37, 2008, Dill, pp. 289-316.
We eat, we grow, we move...and while we may think of these activities in terms of teeth, muscles, and bones, behind all of them, doing all the heavy lifting, are the amazing molecules called proteins.
The National Institutes of Health's primer on How Genes Work describes proteins: "A protein is composed of hundreds or thousands of smaller units called amino acids, which are attached to one another in long chains. There are 20 different amino acids that can be combined to make a protein. The sequence of amino acids determines each protein's unique 3-dimensional structure and its specific function."
Some proteins form antibodies that trap foreign particles like viruses and bacteria rendering them harmless. Others take the shape of enzymes and are responsible for all the chemical reactions in cells. Yet others shape themselves as hormones that carry the messages that ensure the coordination of biological processes. Some form themselves into tubes and sheets that act as structural elements for cells, muscles and bones.
The human genome contains the instructions for the synthesis of 20,000 different proteins.
We use the protein hemoglobin from donated blood to save the lives of the injured. We vaccinate people with proteins from pathogens in order to stimulate the body's natural immune system to make custom proteins to neutralize the pathogens.
Proteins found in nature are incredibly powerful tools. In addition, we have also employed proteins from other living organisms to perform tasks like making our bread rise (gluten) and curdling milk to make cheese (chymosin).
What is we could add to the library of natural proteins by creating new, custom ones?
The dream of custom-designed proteins has been just that, a dream. The barrier to making custom proteins is what cell biologists call "the folding problem."
Once the chain of amino acids has been formed, the chain folds itself into a unique 3-dimensional shape. How the chain folds is determined by the complex interaction of the chemical bonds that link the amino acids together, some parts of the chain are attracted or repelled by other parts of the chain. "The combination of all these molecular forces makes each protein a staggering molecular puzzle." (Zimmer, 2017)
For example, to create a custom protein that would fit precisely into an indentation on the protein casing of a flu virus, a protein designer would need to be able to predict how a complex chain of amino acids would fold into a precise shape to fit the indentation exactly or it will not work.
The image shows how a simple protein folds (and how quickly, in ~20 microseconds). The time is measured in microseconds, or millionths of a second.
In a December 24, 2017 article in the New York Times, science writer Carl Zimmer reports that the folding problem has largely been solved by Dr. David Baker and his colleagues at the University of Washington's Institute for Protein Design.
Among their initial custom proteins is one that blocks the flu virus from invading cells and which in tests provided 100% protection on mice who had been exposed to lethal doses of flu virus. Another protein renders harmless the deadly Botox toxin. Yet another may protect people who are gluten sensitive by chopping up the gluten protein found in wheat-based products.
How Baker and the team solved the folding problem provides insight into how science problems are solved.
There is, first of all, background knowledge.
Proteins are the product of evolution. This means that there are ancestral versions of proteins that can be studied in order to provide information about how a related "descendant" folds.
There is new knowledge that emerges from basic research.
Many proteins share a common structure called a "spiral stretch."
There are certain structures that are shared by many proteins and which has a characteristic series of amino acids. Replicating the series will create the same spiral stretch.
There are new technologies that can be employed to help solve the problem.
In Zimmers account, by the 1990s Baker and his team had begun to employ computer technology to help them with the problem. The team created a computer language called Rosetta to describe how proteins folded and launched it in 1998.
The development of networks of scientists working on the same set of problems.
Baker shared Rosetta with other cell scientists and soon there was a network of scientists who identified themselves as the Rosetta Commons.
As Zimmer describes it, "for twenty years, scientists [of the Rosetta Commons] have been improving the software on a daily basis and using it to better understand the shape of proteins--and how those shapes enable them to work."
Enlist volunteers to contribute (free) computing power.
Using the Rosetta software to stimulate protein folding requires huge amounts of computing power. To build such capacity, Baker created Rosetta@home and recruited computer owners to donate computer processing time on their personal computers and smart phones. "Over the past twelve years, 1,266,542 people have joined the Rosetta@home community."
Look forward! Use new knowledge to solve new problems.
The ability to design custom proteins may lead to "the invention of molecules we can't yet imagine. 'It's a new territory because you're not modeling existing proteins,'" according to Dr. Baker. (Zimmer, 2017)
Some of these new molecules may help fight cancer by first locking on to certain proteins on the surface of cancer cells because they are able to distinguish between cancer cells while leaving healthy cells alone.
David Baker, Director of the Institute for Protein Design at the University of Washington in Seattle, Institute for Protein Design
Theoretical and Computational Biophysics Group (2018). NIH Center for Macromolecular Modeling & Bioinformatics. The University of Illinois at Urbana-Champaign.
Zimmer, Carl. (2017). "Scientists are Designing Artisanal Proteins for Your Body. New York Times, December 25, 2017.
Dr. John Holton
Dr. John Holton joined the S²TEM Centers SC in July of 2013, as a research associate with an emphasis on the STEM literature including state and local STEM plans from around the nation.