NSF CAREER grant: Using rare technology, biophysicist explores molecular recognition

The protein molecules within the human body do the majority of the work of living, said Dr. Nathaniel Nucci. With a five-year National Science Foundation CAREER grant expected to total $749,406, he plans to solve some decades-long mysteries surrounding how these proteins work.

In the field of biophysics, every innovation has the potential for huge implications. What Nucci, an assistant professor in the departments of Molecular & Cellular Biosciences and Physics & Astronomy at Rowan University, discovers may well shine a light on the evolution of cancer and revolutionize how the pharmaceutical industry designs drugs.

The science behind molecular recognition

Without a complicated-sounding concept called molecular recognition, these vital proteins couldn’t accomplish all that it takes to keep a living organism functioning. Somehow, these non-sentient molecules must recognize each other as distinct from the myriad proteins and other molecules that make up the human body and then bind together in precisely the right ways.

“Molecular recognition happens billions of times, every second and in every cell,” Nucci said. “It’s awe-inspiring.”

Decades after its discovery, the phenomenon of molecular recognition still has scientists searching for answers.

“We as a community have been studying this for 50 to 60 years,” Nucci explained. “We know a lot of the rules, but there’s a lot about molecular recognition we don’t understand.”

One of the reasons so many questions remain unanswered is that most researchers have studied proteins in the environment of a diluted solution – and not an environment similar to human cells.

Environmental factors can affect the structure of these dynamic, shape-shifting proteins. Since they can only do their jobs when they’re in the right shape, it’s difficult for researchers in a traditional lab to get a clear picture of the way these proteins work.  

Research in a nanoscale lab

How does one study molecules, which are far too tiny to see with the eye?

Using the same technology as an MRI, a technique called nuclear magnetic resonance (NMR) allows scientists to glean detailed information about the structure of a protein.

“Instead of limbs, it shows us molecules. It’s a difference of scale,” said Nucci. “We’re engineering a simplified nanoscale lab.”

Inside this nanoscale lab, he said, “we can ask questions others can’t about the relationship of protein structure and function — and we can answer them.”

The NMR instrument provides an atomic-level view of protein molecules. Nucci specializes in the use of tiny droplets called reverse micelles to create a simplified cell-like system to study.

What precisely is Nucci looking for in these high-resolution views of these tiny building blocks of life?

“Two things: nanoscale spaces and structures,” he said. “We want to know how spaces impact the way proteins work and how structures change over time.”

With the NMR – a new resource at Rowan and a rare resource at universities across the nation – it’s no longer about merely getting a clear picture.

“Instead of getting snapshots of proteins, we’re trying to understand what the movie looks like,” Nucci said. “We’re looking at the dynamics of how energy moves through a protein.”

Rather, it’s basic research because it delves deep into the exploration of the fundamentals of biophysics to, Nucci said, “move forward the frontier of mankind’s knowledge of biology.”

Nucci and his team are working with a protein known as P53 – the first, and one of the most important, proteins in the study of cancer biology.

“Scientists have known about P53 for 40 years,” said Nucci. This protein could hold the secrets of how cancer evolves, but “no one has investigated P53 the way we are,” Nucci said.

P53 is what scientists call an “intrinsically disordered” protein. Some parts of the protein – the parts that make up the “core” – are well-defined. Other parts are “floppy” and poorly defined, Nucci said.

Diseases like cancer can alter the shape of proteins, changing the ways they work in the body. Delving into the effects of a confined environment on the floppy structure of these parts of P53 may help scientists and clinicians treat cancer someday.

Yet Nucci’s aspirations are even broader.

“Creating a model for understanding how all proteins work can lead to new ways to design drugs that are more specific,” he said.

These medications of the future, founded on the more thorough understanding of protein structure and molecular recognition Nucci hopes to gain, would be better able to bind to the right molecules in the body.

“Most drugs stick to molecules they aren’t supposed to,” Nucci said. “That’s what leads to most side effects.” Developing drugs capable of targeting precisely the right molecules could mean fewer of those side effects, Nucci explained – in virtually any type of medication.

Nucci’s CAREER, his students’ opportunities

In his molecular biophysics course, Nucci’s undergraduate students complete novel research in the classroom.

“To learn science is to do science, and it’s all about failure,” Nucci said. “Students need to understand how to fail and how to fix it.”

That same perseverance he encourages in his students played a crucial role in achieving his CAREER grant.

“Being awarded a CAREER grant is validating,” Nucci said. “It means you’re asking the kind of questions the scientific community finds innovative and important.”

The first step of the project is acquiring the P53 proteins the team will study.

“You can’t just buy the protein. You have to make it,” Nucci said. That’s one of the responsibilities his students have in the project: genetically engineering bacteria to make that protein, and then purifying it for use in the lab.

Since the new NMR instrument won’t be transferred from its current home at the University of Pennsylvania to Rowan until June, the team is also planning a few road trips to the next nearest instrument with comparable abilities… in Manhattan.

“It’s far. It’s inconvenient,” Nucci said. “Getting an instrument of our own was critical.”

The CAREER grant provides funding for two graduate students and three undergraduate students to work on the project.

One such student is Nakoa Webber, a first-year graduate student pursuing her Master of Science in bioinformatics. The 27-year-old from Gibbstown, who completed her bachelor’s degree in translational biomedical sciences at Rowan in 2019, has worked with Nucci since she was an undergraduate.

“Our lab is diverse, with students from many different majors and backgrounds coming together to learn how to think critically and solve scientific problems,” Webber said, noting the students will benefit directly from the CAREER grant Nucci was awarded.

“It is incredibly exciting to receive funding to continue our work studying the complex effects of confinement on protein stability,” Webber said. “This grant will give us access to additional scientific tools, allowing us to take our learning and research to the next level, and it will allow more students to have that same experience and to continue driving meaningful research projects forward.”

To Nucci, the opportunities the CAREER grant affords students may be the best part of the award.

“The grant is exciting, but it’s not just about the innovation. It’s about the people,” he said. “For the next five years, I know I’ll be able to support the students – and that’s the most important thing we produce at Rowan. We’re educators first.”