Imperfect polymer sequences still control protein function, revealing new design rules

What happens when a scientific problem seems too complex to solve precisely, yet understanding it could reshape how researchers design new materials and medicines? For decades, much of the polymer science community has relied on a "good enough" approach to a stubborn problem: binding a polymer to a protein in a precise way that reliably controls how the protein behaves.

Polymers—long chains built from repeating small molecules called monomers—make up much of the material world, from plastic bags and clothing to advanced medicines. Designing those chains to interact with proteins, however, has pushed the limits of precision chemistry.

In a study published in Angewandte Chemie, chemist Darwin Gomez, a member of Adrian Figg's lab, and fellow Virginia Tech researchers Ronnie Mondal and Swarnadeep Seth demonstrated that even when a polymer lacks a perfectly tailored sequence, the protein it binds to can still function as intended.

Compare a protein's intricate surface to a rock wall full of routes, grooves, and footholds. Building a polymer that follows the "perfect" route across that surface is nearly impossible.

As a result, researchers often use larger, less-precise polymers with many potential footholds to increase the likelihood of forming the pathway and getting the molecule to behave how they intend. However, that approach leads to difficulties and large estimates.

Gomez, Mondal, and Seth worked to make a more "perfect" route along the rock wall, endeavoring to find ways to craft a more exacting polymer.

After thousands of reactions and countless hours of work, Gomez finally hit a breakthrough when his proteins started to light up the way he wanted them to—the protein was behaving as desired when the polymer bonded to it.

He found that while it is still nearly impossible to create a polymer so exact, he can get a polymer more specific and that the overall composition of a polymer matters much more than scientists originally thought.

"The paper is a demonstration that binding a polymer to a protein is, yes, influenced by its specific composition, but not necessarily on its specific sequence," Gomez said.

Teamwork across chemistry

The project's success grew from collaboration across chemistry, chemical engineering, and computational science.

Swarnadeep Seth, part of Sanket Deshmukh's lab in the Department of Chemical Engineering, performed specialized simulations called well-tempered meta dynamics that further explored the "rock wall" of the protein.

"The simulations were essential—meta dynamics did the heavy lifting by efficiently exploring the vast molecular landscape," Swarnadeep said.

Ronnie Mondal, a graduate student in Valerie Welborn's group, contributed simulations that confirmed how the experimental system was behaving. Computational simulations "allowed us to confirm patterns that the experimental group was seeing, which helped tie the story together," he said.

Together, the team developed a clearer picture of how to design polymers that bind effectively to proteins—a key step toward creating new materials and biomedical tools.