Science Success Story
Supercomputing the Secrets of the Inner Ear
XSEDE-allocated supercomputers aid in study of key proteins involved in hearing and balance
Faith Singer-Villalobos, Texas Advanced Computing Center (TACC)
|Credit: Marcos Sotomayor, The Ohio State University|
Marcos Sotomayor, a researcher in chemistry and biochemistry at The Ohio State University, and his colleagues are studying cadherin-23 (CDH23) and protocadherin-15 (PCDH15), two large proteins involved in hearing loss and balance disorders, using supercomputing resources allocated through the National Science Foundation-funded Extreme Science and Engineering Discovery Environment (XSEDE).
If a person doesn't have these proteins they cannot hear. And they won't have a sense of balance either because there won't be electrical signals coming from the inner ear for the brain to process," Sotomayor said.
When sound vibrations reach the inner ear, fine protein filaments called tip links stretch and open cochlear hair-cell channels that trigger the electrical signals that mediate sensory perception. Similarly, vestibular hair cells use tip links to sense mechanical stimuli produced by head motions.
Hearing turns physical movement into the electrical signals that make up the language of the brain. These signals translate vibrations into what we experience as sound," Sotomayor said. "The main prediction in this research is related to how you can transform sound into an electrical signal that your brain can understand. We're studying this at a molecular level.
|Marcos Sotomayor, a researchers in chemistry and biochemistry at The Ohio State University|
In a paper published in PNAS in October 2020, Sotomayor and team present multiple structures, models, and supercomputer simulations that depict the lower end of the tip link. Their work includes the complete PCDH15 ectodomain, which opens cochlear and vestibular channels to initiate signal transduction.
These models show an essential connection between CDH23 and PCDH15 and various sites that are mutated in inherited deafness. The supercomputer simulations reveal how the tip link responds to the force from vibrations to mediate hearing and balance sensing.
The inner ear is made up of the cochlea and the vestibular system. The cochlea is for your sense of hearing. The vestibular system is in charge of maintaining balance. In both cases, there is a mechanical stimulus, a pressure wave or motion that needs to be transformed into an electric signal. This happens within the sensory cells of the cochlea and the vestibular system, called hair cells because of hair-like structures that sit atop of the cells and form a bundle essential for hearing and balance.
When the hair-cell bundle moves, the tip links stretch and open a channel. Charged ions rush in. That is the first electrical signal that the inner ear starts to process.
The researchers expressed the proteins, crystallized them, and then sent these crystals to a synchrotron to obtain diffraction patterns and structures. Using these structures they built models with more than one million atoms to simulate using supercomputers.
We needed supercomputing resources to make a physics-based molecular simulation of the effect of sound on tip links. Without these systems we wouldn't have been able to look at the dynamics of this filament. And we wouldn't have been able to build the model of the entire PCDH15 ectodomain. -- Marcos Sotomayor, The Ohio State University
|Two cadherin-23 molecules (light and dark blue) engage in 'handshake interactions' with two protocadherin-15 molecules (light and dark magenta). Credit: Choudhary et al., PNAS 2020.|
How XSEDE Helped
Sotomayor and team used the XSEDE environment, which organizes, integrates, and coordinates the sharing of advanced digital services, including supercomputers and high-end visualization and data analysis resources, to support science across the nation.
The researchers relied upon the XSEDE-allocated Stampede2 system at the Texas Advanced Computing Center (TACC) and the Bridges system at the Pittsburgh Supercomputing Center to start to understand the dynamics of the tip-link proteins.
We needed supercomputing resources to make a physics-based molecular simulation of the effect of sound on tip links," Sotomayor said. "In this paper, we were able to build a structural model of the entire PCDH15 ectodomain using simulations to test its strength and elasticity.
The simulations are costly in terms of computing time. For instance, in some cases, the researchers ran the simulations for two to three months on the supercomputing resources.
"Without these systems we wouldn't have been able to look at the dynamics of this filament. And we wouldn't have been able to build the model of the entire PCDH15 ectodomain," Sotomayor said.
Sotomayor and his team are looking forward to the opportunity to scaling up their simulations to larger, more capable systems. "TACC now has the Frontera supercomputer, which can be applied for independently. Frontera is a system we'll definitely use in the future."
This work was supported by the Ohio State University; the National Institutes of Health–National Institute on Deafness and Other Communication Disorders (R01 DC015271); and the National Science Foundation through the Extreme Science and Engineering Discovery Environment (XRAC MCB140226).
The Ohio State researchers who worked on this study are Deepanshu Choudhary, Yoshie Narui, Brandon L. Neel, Lahiru N. Wimalasena, Carissa F. Klanseck, Pedro De-la-Torre, Conghui Chen, Raul Araya-Secchi, Elakkiya Tamilselvan, and Marcos Sotomayor.
At a Glance
- Researchers are studying cadherin-23 (CDH23) and protocadherin-15 (PCDH15), two large proteins involved in hearing loss and balance disorders, using supercomputing resources allocated through XSEDE.
- In PNAS in October 2020, they present multiple structures, models, and supercomputer simulations that depict the lower end of the tip link. Their work includes the complete PCDH15 ectodomain, which opens cochlear and vestibular channels to initiate signal transduction.
- The researchers relied upon the XSEDE-allocated Stampede2 system at TACC and the Bridges system at PSC to start to understand the dynamics of the tip-link proteins.
- They are looking forward to scaling up their simulations to the Frontera supercomputer at TACC.