As a structural bioinformatician, my work is to do computational modeling and molecular biology, where understanding protein structure is central to solving therapeutic problems. Over time, I have been fortunate to apply this perspective to the field of nanobody design, working on molecules where structure, stability, and function are tightly linked. I am grateful for the opportunity to work in this space, where each project contributes not only to my own learning, but also to the broader goal of developing precise and effective cancer therapeutics.
My work as a structural bioinformatician focuses on nanobody design and on understanding how compact molecular architectures give rise to complex structural and dynamic behavior. Nanobodies are often described as simplified antibodies, but in practice they demand more precision, not less. Their success in cancer therapy depends heavily on how carefully their structure, stability, and interactions are engineered.
"Nanobodies are often described as simplified antibodies, but in practice they demand more precision, not less. Their success in cancer therapy depends heavily on how carefully their structure, stability, and interactions are engineered."
Nanobodies originate from the variable domains of camelid heavy-chain–only antibodies, found in llamas, alpacas, and camels. In simple words, these animals naturally produce a special kind of antibody that works with only a single binding unit instead of the usual two. This makes nanobodies much smaller than conventional antibodies, while still allowing them to recognize targets with high specificity. Their single-domain nature allows them to bind regions on cancer-associated proteins that conventional antibodies often cannot reach. This ability is powerful, but it comes with constraints. When a molecule is this compact, even small changes in the framework or binding loops can have a large impact on stability or affinity. There is very little room for error.
Humanization is where this becomes especially clear. In simple terms, humanization means modifying the nanobody so that it appears more “human-like” to the immune system. Because these nanobodies are camelid in origin, they cannot be used directly in patients without modification. Early on, I learned that treating humanization as a simple sequence replacement problem often leads to failure. A residue that looks harmless on paper can quietly destabilize the fold or alter the binding geometry. Over time, my approach shifted toward treating humanization as a structural problem, where each framework change is evaluated based on its role in supporting the overall shape and the antigen-binding loops.
Docking is usually the first step to understand how a nanobody might bind its target, but docking alone rarely tells the full story. The models look convincing, yet they are frozen in time. Molecular dynamics simulations are where those assumptions are tested. Watching a nanobody–antigen complex evolve over time often reveals weaknesses that static structures hide—loops that drift, contacts that fail to persist, or interfaces that slowly loosen.
By combining structure-guided humanization with docking and simulation, I try to narrow the gap between a promising idea and a molecule that can survive closer scrutiny. Not every design works. Many fail quietly in simulation. But when a nanobody holds its structure, maintains its binding, and behaves as expected, it feels like progress. In cancer therapeutics, where precision matters, these small, steady steps are often what make the difference.
- Nanobody Engineering
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