Head of Research Team Peter Wolynes: 'We think that this may be a very common functional mechanism in protein dynamics.'

Researchers at Rice University have made a groundbreaking discovery, unraveling the intricate dynamics behind estrogen regulation in the body, which could set the stage for better breast cancer prevention therapies, the university said in a press release. 

Through their research, the team of scientists identified a unique "string puppet" mechanism employed by estrogen receptor molecules, shedding light on how these receptors manipulate their structure to regulate gene expression, the release said. Peter Wolynes, a corresponding author of the study and a theoretical physicist at Rice, and his team of Rice graduate students focused on the structure and function of estrogen receptor alpha proteins, which consist of two domains.

“This molecule has two regions or domains that normally are not touching each other,” Peter Wolynes, a corresponding author of the study and a theoretical physicist at Rice, said in the release. “Instead, they're separated by two stringlike structures. The puzzle was, how do these two domains communicate with each other? How is the information that a hormone is bound conveyed to the domain that binds DNA?”

The scientists worked to figure out how these domains communicate and convey information when the hormone is bound. Using software called AWSEM (Associative memory, Water-mediated Structure, and Energy Model), which the team developed to predict the structure and behavior of proteins, the researchers simulated the dynamics of the estrogen receptor molecule, the release stated. They found that when the ligand binding domain, responsible for hormone attachment, changed its structure, it rotated and moved the string-like structures further apart. As a result, the strings connecting the domains shortened, bringing the ligand binding domain into closer contact with the DNA binding domain, similar to how a puppet master manipulates a marionette.

Wolynes has compared the string-like structures to the arms of an octopus, which find and grab onto something before organizing themselves. Wolynes previously discovered this mechanism, called fly-casting, which has been observed in various systems. The team's findings suggest that the two string-like structures cooperate like a marionette, a concept that had not been previously considered. 

“We think that this may be a very common functional mechanism in protein dynamics,” Wolynes said. “There are a lot of other hormone receptors that have a similar organization of structured domains connected by strings.” 

The implications of this research extend beyond breast cancer. According to the release, estrogen receptor mutations are also associated with other diseases and types of cancer. 

Protein structure prediction has gained attention with the development of DeepMind's AlphaFold, Wolynes said. AlphaFold predicts the shape a protein will morph into, while AWSEM predicts both the folded shape and the behavior and interaction within the molecular environment. 

Wolynes is Rice’s Bullard-Welch Foundation Professor of Science. He is a professor of chemistry, biochemistry and cell biology, physics and astronomy and materials science and nanoengineering, and is co-director of the Center for Theoretical Biological Physics at Rice. 

The study was published in the Proceedings of the National Academy of Sciences. It was supported by the G. Harold and Leila Y. Mathers Charitable Foundation, the National Science Foundation, and the D.R. Bullard-Welch Chair at Rice University.