Tulane Researcher Receives NSF CAREER Award to Unlock the Physics Behind How Proteins Work

Shuaihua Gao, an assistant professor in the Department of Chemical and Biomolecular Engineering at Tulane University, has received a National Science Foundation CAREER Award for a five-year research project that could change how scientists approach enzyme design. The award, one of NSF's most prestigious recognitions for early-career faculty, will fund her project, "From Energy Flow to Function: A Biophysical Framework for Rational Enzyme Evolution," through May 2031.

Gao's path to protein science began during her undergraduate years, when she was drawn to pharmaceutical engineering by the idea of being able to design and make medicines.

That early curiosity led her into doctoral research, where she discovered a novel DNA sequence for a unique protein and developed high-throughput screening methods, used X-ray crystallography to determine three-dimensional protein structures, and applied directed evolution to make proteins more useful for pharmaceutical applications. The protein she identified was used to produce precursors for antiviral and antimicrobial drugs.

But something was still missing. She could make proteins work. She did not yet fully understand, at a physical level, why they worked.

That gap sent her to the University of California, Berkeley, for her postdoctoral training under enzymologist and biophysical chemist Judith Klinman. There she was introduced to a powerful analytical technique called temperature-dependent hydrogen-deuterium exchange mass spectrometry, or TDHDX-MS, which would become a cornerstone of her current research.

At the center of Gao's NSF-funded project is a question that sounds almost physical in the classical sense: how does heat move through a protein?

"Imagine you have a protein and you put it into a cell. There's heat, there's energy, there's temperature. Then heat from the environment transfers into the interior of the protein to perform catalysis or chemical reactions."

Proteins are not symmetrical structures. They are complex, asymmetrical, and their behavior during catalysis is not well understood at the level of energy transfer. Gao's project aims to map the pathways through which heat travels inside a protein and to use those pathways as a guide for designing better enzymes.

"The unique angle of this research is to discover or uncover the heat transfer pathways in protein structure. That way, we can use those pathways to guide us to design proteins in a faster, more rational manner."

Today, most enzyme design still relies on trial and error. Gao wants to replace that with a predictive, physics-based framework built on real structural and energetic data.

The potential reach of this research is wide. Proteins, Gao explains, offer a cleaner alternative to the chemicals and heavy metals often used in industrial catalysis. If scientists can design them with greater precision, the applications span sectors.

"Imagine you can use proteins to make chemicals for industry, produce pharmaceuticals for health, and degrade harmful chemicals in the environment, such as forever chemicals."

The current research focuses on a non-native myoglobin engineered to produce precursors for antiviral and antimicrobial drugs. But Gao's lab is already extending the biophysical tools developed through this project to other problems, including cancer biology and a neurodevelopmental disease tied to mutations in a protein called DDX3X.

DDX3X is an RNA helicase, a protein that regulates which genes are expressed in the body. When children carry mutations in the gene that produces it, their RNA metabolism is disrupted, affecting their intellectual development. Currently, there is no treatment.

"Because people don't know how fundamentally this is triggered and what is causing the disease, there's no treatment or cure. The only thing people can do is support."

Gao's lab has developed preliminary data on DDX3X and is preparing to submit a grant to the National Institutes of Health to pursue that work further.

The NSF CAREER Award requires a significant education component, and Gao has structured hers around connecting students at every level to the real science happening in her lab.

"Students can learn – this is a protein, everyone has it. But how do I actually use it for applications or how do I study it? We are also working with carbonic anhydrase and we can use carbonic anhydrase to make a CO2 capture, which has global warming related applications. So that way they can use real data and connect what they learn in a classroom to real world applications."

Beyond her courses, Gao's lab partners with Tulane's K-12 STEM education program, hosting workshops each year to introduce young students to protein science and encourage them to pursue STEM fields in college. The program also includes outreach to local community colleges, with plans to bring students to Tulane's campus for summer research experiences, giving them a pathway from a two-year program into a four-year STEM degree.

Gao was clear about the weight of what award means to her personally.

"It's definitely a huge relief, and an important milestone for securing federal funding. Since I started as an assistant professor about two and half years ago, every day, my mind has been thinking about how to get federal funding."

More than the funding itself, she says the award validates the direction she has been working toward since her days in the lab as a graduate student: bringing fundamental physics and applied protein engineering together under one roof.

"I am a biophysical chemist and a protein engineer. I do fundamental science. I also do translational research and then try to combine them. This award gave us the support to pursue the long-term goals and ideas we have in my lab."

Gao was equally quick to share the credit.

"I want to attribute this award to all my mentees, graduate students, and postdocs. They helped me establish my lab when there was nothing in the lab about two and a half years ago. I'm a really lucky PI who has talented and hard-working students who help make this come true.”

She also acknowledged the colleagues and faculty members in the Department of Chemical and Biomolecular Engineering who supported her as she built her research program. "[I’ve had] tremendous support from the faculty members at CBE. My friends and my colleagues, they helped a lot. I am very grateful to them."

Five years and a foundational framework in protein biophysics now lie ahead. For Gao, the science is only getting started.