Turning Atomic Insights into Medical Innovation
Making the Invisible, Visible
Proteins are essential to life, yet many of them remain scientific mysteries, especially those embedded in cell membranes. These membrane proteins control bodily functions such as sensing light, transporting water and responding to hormones, but they’re notoriously difficult to study.
At the University of Guelph, Dr. Vladimir Ladizhansky and Dr. Leonid Brown from the Department of Physics are using magnetic resonance techniques and a deep curiosity for how biology behaves at the atomic level to advance our understanding of this challenging and elusive area of biophysics.
“Our field is about turning what’s invisible into something we can actually understand,” says Brown. “You’re looking at individual atoms and asking how they create life’s most essential processes.”
Using Magnetic Fields to Map Proteins
The team focused on Anabaena Sensory Rhodopsin (ASR), a light-sensitive membrane protein found in cyanobacteria. ASR serves as a model for understanding how proteins embedded in membranes function, particularly those that respond to environmental signals such as light or pressure.
To explore ASR’s structure, the team used Paramagnetic Relaxation Enhancement solid-state Nuclear Magnetic Resonance (NMR). This approach involves introducing paramagnetic tags into defined locations in the protein. These tags supress signals from nearby atoms and provide long-range distance information that can be used to determine membrane protein structure.
“Membrane proteins are difficult to work with because they don’t dissolve in water like most proteins,” says Ladizhansky.
“We use solid-state NMR to study them in lipid environments that mimic biological membranes, without disturbing their structure.”
Their refined model of ASR showed a significant improvement in the alignment of protein subunits and the interactions between individual helices – a critical advancement since even minor inaccuracies might lead to incorrect predictions about how the protein’s behaviour and its interactions with other molecules.
The research, led by former MSc student Raoul Vaz, made effective use of relatively limited data thanks to the efficiency and accuracy of their Paramagnetic Relaxation Enhancement-assisted workflow.
Unexpected Discoveries Can Advance Science
During earlier experiments, the researchers discovered that ASR formed a trimeric structure (a three-unit assembly) in membranes, which sharply contrasts with the dimeric arrangement observed by X-ray crystallography. According to Ladizhansky, such serendipitous and unexpected findings are exciting for researchers, as they could lead to new scientific discoveries.
More recently, the team observed unexplained signals in their data, suggesting that small, non-proteinaceous molecules may be binding to ASR. This prompted a new line of investigation aimed at identifying these foreign molecules, and understanding how they interact with the protein.
Applying Results to Human Health
Ladizhansky and Brown are applying their expertise to the protein responsible for regulating water reabsorption in the kidneys, human aquaporin 2. When this protein doesn’t function properly, it can result in nephrogenic diabetes insipidus, a rare condition where the body loses large amounts of water, leading to dehydration and electrolyte imbalance.
With new seed funding from the Kidney Foundation of Canada, the team is now building models of this protein to determine how structural mutations affect its function and, importantly, its intracellular transport.
Their findings could pave the way for future therapeutic strategies, including efforts to "rescue" partially functional proteins by restoring their correct localization.
Importance of Interdisciplinary and Industry Collaboration
The grant is a launching pad not just for research, but also for collaboration. The team plans to work with cell biologists and clinical researchers to bridge the gap between fundamental structural biology and real-world biomedical applications.
The long-term vision is to connect atomic-level insights to what happens in the human body, says Ladizhansky.
Both researchers credit the interdisciplinary nature of their research for its success. Combining physics, biology and chemistry allows them to tackle questions that no single field could answer alone.
Ladizhansky and Brown also credit the efforts of students in their biophysics labs to recent research advancements.
“We tell students, if you're studying linear algebra or quantum mechanics and wondering where it applies – this is it,” says Brown. “Modern biology is impossible without physics.”