There’s an important component to brain health in our heads – a complex, tightly packed barrier that surrounds the brain called the blood-brain barrier (BBB). This powerful protector makes sure nothing harmful, such as toxins, gets into our brains. But there’s a downside – it also makes it hard to deliver much-needed medicines to their targets in the brain.
Currently, 98% of drug candidates in early phases of the drug industry cannot cross the BBB, creating a significant challenge for the development of treatments for neurological (Alzheimer’s and Parkinson’s diseases), psychiatric (depression, anxiety) and brain cancer diseases. Think of the BBB as a bouncer at a popular nightclub. The bouncer lets in necessary nutrients, like Omega-3 fatty acids, which are essential for brain development and health, because they’re dressed just right. But the brain club is highly exclusive, and the bouncer sees almost everything else as a problem partier, even medicine that could be life-saving.
Researchers from the Weill Medical College of Cornell University (Weill Cornell Medicine) are working to discover what happens at the BBB and how that bouncer chooses what to let in and what to deny entry. They’ve been able to make great strides in their work due to the powerful ACCESS-allocated resource, Delta, at the National Center for Supercomputing Applications (NCSA).
The bouncer analogy is how Margarida Rosa, a doctoral candidate at Weill Cornell Medicine, describes the process of moving molecules past the BBB to laymen to help them understand it better. She’s working with George Khelashvili, Ph.D, an associate professor at the Department of Systems and Computational Biomedicine at Weill Cornell. In the lab, the research team investigates a special protein that acts like a kind of VIP pass through the usually restrictive BBB. This protein is called MFSD2A (Major Facilitator Superfamily Domain 2A). It’s found in the cells lining the blood vessels of the brain within the BBB, and, importantly, it’s what escorts Omega-3 through the barrier. This protein system is of high interest to the team at Weill because if they can figure out how MFSD2A escorts Omega-3, they could apply that knowledge to make it escort specific drug-like molecules past the BBB, making many medicinal treatments much more effective.
This is where MFSD2A could be the key to getting medicine directly to the brain. Research has shown that MFSD2A can transport more than Omega-3s through the BBB – certain drugs, such as tunicamycin antibiotic, could also be carried through – but the protein won’t carry just any molecule. Rosa and Khelashvili are working to uncover the specific qualities a molecule must possess to be carried by MFSD2A, with the goal of designing small therapeutic drugs that can pass safety through the BBB.
To perform this research, the team utilized research computing to create highly detailed simulations that allowed them to study how MFSD2A operates at an atomic level.
“I use computer simulations to get a close-up view of how this protein moves molecules into our brain and keeps others out,” said Rosa. “My aim is to find out the important features that make a molecule ‘party-ready’ for the brain. Just like wearing the right outfit might get you into a party, certain features of a molecule, such as size, charge or hydrophobicity, can make it more likely to be transported by MFSD2A.”
By analyzing these long simulations with advanced computational biophysics and machine learning approaches, the team can train computer models to recognize the differences between molecules that MFSD2A will transport and those it won’t. “Once I figure out these differences,” explained Rosa, “I can then modify the molecules that usually cannot enter the brain by adding features that will make them more likely to be transported. I will ‘dress them up’ in a way that makes MFSD2A want to let them in. Then I can test whether these ‘outfits’ persuade the bouncer (BBB) to let these molecules enter the brain through MFSD2A.”
Much of this work would not have been possible without the resources that NCSA can provide. Khelashvili and Rosa used the U.S. National Science Foundation’s ACCESS program to secure time on the Center’s GPU-based supercomputer, Delta.
Uncovering fundamental functional mechanisms in the biological systems we study, such as MFSD2A transporter, presents a substantial challenge due to the sheer size and complexity of these systems. With the help of the powerful computational resources provided by ACCESS we are able to overcome this challenge. The ACCESS infrastructure allows us to conduct large-scale molecular dynamics simulations and to analyze the data these simulations produce with state-of-the-art computational biophysics and machine learning/artificial intelligence approaches. This enables the fundamental knowledge we seek to understand not only how MFSD2A protein works but also how it can be repaired when its mechanism malfunctions.
–George Khelashvili, Weill Cornell Medicine
“MD simulations are used to model the behavior of atoms and molecules over time, giving very detailed and important information you cannot obtain from experiments. But biologically meaningful events often occur on the microsecond to millisecond scale, well beyond the reach of standard simulation techniques,” said Rosa. “MFSD2A is also a large and complex system (approximately 230,000 atoms when embedded in the membrane and immersed into a solution environment) with rare transport events, requiring access to the latest GPUs, parallel computing infrastructure and enhanced sampling techniques, all available through ACCESS.”
For more information, you can find the full story here: Breaking Barriers – Delta Helps Reveal the Brain’s Gatekeeper.
For those interested in more detailed information about this research, in addition to the forthcoming publication, there are several articles of note that the team has published:
Structural Basis of Omega-3 Fatty Acid Transport across the Blood–Brain Barrier, Nature
Substrate Binding-Induced Conformational Transitions in the Omega-3 Fatty Acid Transporter MFSD2A, NatureCommunications
Automated Collective Variable Discovery for MFSD2A Transporter from Molecular Dynamics Simulations, Biophysical Journal
Resource Provider Institution(s): National Center for Supercomputing Applications (NCSA)
Resources Used: Delta
Affiliations: Weill Medical College of Cornell University
Funding Agency: NSF
Grant or Allocation Number(s): BIO240348
The science story featured here was enabled by the U.S. National Science Foundation’s ACCESS program, which is supported by National Science Foundation grants #2138259, #2138286, #2138307, #2137603, and #2138296.