Protein Interactions: Fordham’s Own Shaping Molecules of the Future

By: Sophie Epstein

Proteins are, of course, so much more than what we think of when we drink a shake in the morning. These complicated polymers are not just limited to nutrition but carry out countless essential functions in the natural world. Yet, beyond their natural functions, chemists are even still finding new ways to use them to solve problems. Dr. Sawyer explains that protein-protein interactions “dictate most things that you experience every single day.” He is a bioorganic chemist who we have recently welcomed to the Fordham Chemistry Department, and his work hopes to “circumvent many of the limitations that exist with proteins.” Since proteins rarely act on their own, the interactions between them are essential to this. These interactions can, and frequently do, go awry, leaving chemists with the task of searching for the best way to encourage them to return to their normal, functional state. Because healthy cellular behavior requires such a delicate balance of said interactions, certain human diseases, like cancer, may result in an overproduction of certain proteins that throws off this finely tuned equilibrium. This is just one example of a situation where a protein-protein interaction may behave in a manner that must be adjusted, and where it may be imperative to do so. The structure of proteins can make them difficult to manipulate, though, and this is where Dr. Sawyer’s lab becomes essential.

By molecular standards, proteins are massive — they can be composed of thousands upon thousands of atoms. Dr. Sawyer describes these substances as “fascinatingly complex”: somehow, the entirety of a protein has come together in a perfectly particular way. Proteins are held in shape by hundreds, or even thousands, of weak interactions that fold the protein into specific shapes that are able to carry out specific functions. Sometimes these large proteins can be used to solve the issues that arise from faulty interactions, and the aforementioned balance can be restored. However, their great size can come at a cost. Each protein’s surface is polar. This, in addition to its size, makes it difficult for a protein to pass through membranes of cells, which are non-polar. These membranes are hydrophobic, or repelled by water and other polar molecules. Yet inside the cells is where some key protein-protein interactions of interest occur. Since many proteins must thus access the inside of the cell, but often cannot, Dr. Sawyer and his team wondered how we can use organic chemistry to create smaller molecules that circumvent this delivery problem. More precisely, with a specific protein target in mind, how can we design molecules to modify their function for a potential biological or clinical application?

However, despite their large and complex structure, the functional part of a protein is on the surface and may be only ten or twenty out of the hundreds of amino acids that constitute its whole structure! The remaining ones merely serve as a “scaffolding” to support the functional ones in carrying out their duty. Dr. Sawyer’s lab has ultimately set out to “distill” the protein to only this functional fragment, often referred to as a peptide. Peptides derived from a protein can fit themselves onto the large surfaces of other proteins that they will interact with, essentially mimicking a whole protein in this interacting pair. This makes them great at competing with other proteins to restore the delicate balance between interacting proteins. In Dr. Sawyer’s words, the goal is to “understand how synthetic, organic strategies can be used to accomplish with five atoms what normally would need a hundred atoms.”

Peptides can be encouraged to adopt certain shapes that complement their protein targets when modifications are made beyond the standard, existing set of 20 amino acids that compose almost all proteins. With this array of new “pieces,” so to say, identifying when to use which ones to produce a protein structure that can dictate a particular function has become a goal of Dr. Sawyer’s lab. This process can be immensely challenging, however, because making these structural changes is not always as simple as substituting one piece for another. Molecules can express different shapes, and these change on a whim. These dynamics consequently affect the function, and the team must constantly reevaluate their process, since these changes could mean they have oversimplified their process or left something out. This makes the process of elimination a notably effective strategy for determining the ideal alterations to make. In this research process, figuring out which pieces do not work can often be as valuable as finding pieces that do work, providing hints toward general approaches that may work across many different peptides and proteins. 

However, challenges are not just limited to those in the lab, as all researchers have realized this past year. The COVID-19 pandemic has restricted the use of research space and limited opportunities to create potential collaborative opportunities. But Dr. Sawyer has expressed how the chemistry department here at Fordham has been welcoming to him as a new faculty member, and that while these challenges have made it harder to get started, he knows that it will not limit the discoveries that his growing research group can ultimately make. We are excited to see what developments come next in the wide world of peptides and proteins.

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