The Building Blocks of Nature: Rise of Protein Design

By: Eesha Chandolu

While many of us struggle to assemble IKEA furniture without leftover screws, researchers in computational biology are assembling something far more complex: brand-new proteins that have never existed before. At UNC’s Department of Biochemistry and Biophysics, one professor is helping lead this shift, using powerful computational tools to design molecular machines that could shape the future of medicine. It is a quiet revolution, but a profound one—biology is beginning to look less like observation and more like engineering.

Headshot of Dr. Brian Kuhlman

Dr. Brian Kuhlman’s path into this field began during his postdoctoral work, where he contributed to the development of Rosetta, one of the world’s most influential software platforms for modeling and designing protein structures. At the time, predicting how a simple chain of amino acids folded into a precise three-dimensional shape was considered one of the hardest problems in biology. Today, the field has moved beyond prediction and into creation. Scientists can now design proteins from scratch, tailoring them to perform specific tasks that natural evolution never intended.

The motivation for designing proteins instead of only studying natural ones is both scientific and practical. Natural proteins evolved to balance many competing demands—survival, adaptability, and efficiency. Designed proteins, however, can be optimized for a single purpose. Rather than modifying nature’s tools, researchers can build new ones specifically tailored to solve modern medical and scientific challenges.

Proteins are often described as the body’s nanomachines because they perform nearly every function inside our cells. Enzymes break down food, antibodies defend against disease, and signaling proteins coordinate communication between cells. A protein’s shape allows it to perform these tasks. Protein design focuses on choosing amino acid sequences that fold into precise three-dimensional structures capable of performing new functions. By designing new shapes, scientists can create entirely new biological tools.

Much of this work begins not at the lab bench, but on powerful computing clusters.Graduate students create thousands of possible protein sequences using powerful computer programs and high-speed computing systems. Promising protein candidates are synthesized into DNA and inserted into living cells, which then produce the proteins. After isolating the proteins, researchers test them to see if they work as expected. The process can take months and often requires multiple rounds of refinement. Translating a computational design into a functioning protein remains one of the field’s biggest challenges, as proteins must remain stable, soluble, and effective within complex biological environments.

One of the lab’s most innovative research areas involves light-activated protein switches. These proteins change shape when exposed to specific wavelengths of light, allowing scientists to control biological processes with remarkable precision. Researchers can insert these proteins into cells and activate them under a microscope, enabling real-time studies of how protein activity influences cellular behavior. In neuroscience, these tools are helping scientists explore how neurons communicate and form connections, providing new insight into how the brain functions.

The lab also focuses on antibody engineering, particularly bispecific antibodies used in cancer immunotherapy. Traditional antibodies bind to a single target, but bispecific antibodies are engineered so each arm binds a different molecule. One arm can attach to a cancer cell while the other binds to a white blood cell, bringing immune cells directly into contact with tumors. This strategy has become a powerful approach in modern cancer treatment, and protein design has helped make these therapies more feasible to develop.

Collaboration plays a central role in this research. Protein design connects many scientific disciplines, from microbiology to oncology. The lab collaborates with researchers studying viruses to design improved vaccines and with cancer scientists who test antibody therapies in animal models. Artificial intelligence has also become an important partner, accelerating protein design by improving structure prediction and expanding the range of biological problems scientists can tackle. Despite these advances, curiosity remains at the heart of the research process.

Looking ahead, computational protein design has the potential to transform medicine in profound ways. Personalized cancer treatments may one day target the unique mutations present in each patient’s tumor. Vaccine development could become faster and more precise by designing proteins that train the immune system more effectively.

For students interested in entering the field, the advice is clear: build a strong foundation in biology while developing computational skills. The field is evolving rapidly, creating new opportunities for the next generation of scientists.

Early in his career, a colleague once asked why Dr.Khulman pursued this research. At the time, he admitted he did not have a clear answer. Today, he wishes for his designed proteins to have useful applications in research, medicine, and industry. It is a modest goal that reflects a larger truth: scientific progress often happens quietly, through years of persistence, collaboration, and curiosity.