Conduit, created by MIT graduate (and current CEO) Ryan Robinson, was founded in 2017. But it might not have been until a few years later, when the pandemic started, that Conduit may have found its true calling. While Conduit’s commercial division is busy developing a Covid-19 test called nanoSPLASH, its nonprofit arm was granted access to one of the most powerful supercomputers in the world—Frontera, at the Texas Advanced Computing Center (TACC)—to model the “budding” process of SARS-CoV-2.

Budding, the researchers explained, is how the virus’ genetic material is encapsulated in a spherical envelope—and the process is key to the virus’ ability to infect. Despite that, they say, it has hitherto been poorly understood:

The Conduit team—comprised of Logan Thrasher Collins (CTO of Conduit), Tamer Elkholy, Shafat Mubin, David Hill, Ricky Williams, Kayode Ezike and Ankush Singhal—sought to change that, applying for an allocation from the White House-led Covid-19 High-Performance Computing Consortium to model the budding process on a supercomputer.

The allocation was granted, with the team getting access to TACC’s Frontera system, a 23.5-Linpack petaflops Dell system that ranked 13th on the most recent Top500 list. On Frontera, they used the GROMACS molecular dynamics package to run simulations of the viral molecules involved in the budding process—specifically, the virus’ membrane (M) and envelope (E) proteins, along with a cell membrane—with each simulation containing around half a million atoms modeled across 800 million time steps. They simulated a variety of protein configurations, including a membrane-only system; a system with four E protein pentamers; a system with a single M protein dimer; a system with four M protein dimers; and a system with three M protein dimers and one E protein pentamer.

“It was an honor to utilize one of the world’s most powerful high-performance computing machines for our Covid-19 research,” Collins told HPCwire in an email interview. “We were nervous when the Frontera system was temporarily unavailable during the snowstorms last year, but through our determination and organized communication, we completed our simulations in a timely fashion and were able to make our results available to help combat the ongoing pandemic.”

The results in question were detailed in a paper published in the December issue of the Journal of Physical Chemistry Letters. The researchers found that the M and E proteins facilitated different parts of the budding process, with the M protein in particular inducing membrane curvature. “One of the most notable outcomes of our simulations was that the [four M protein dimer] system gained a substantial degree of global curvature over time, while other systems such as mem had very little curvature,” they wrote. Through quantitative analyses comparing the simulations, they concluded that “E proteins likely do not induce substantial curvature, that isolated M proteins create bulges in the membrane, and that many M proteins together can act together to induce larger amounts of curvature.”

In sum: the curvature caused by the M protein (roughly 300 times more plentiful than the E protein) wraps the cell membrane around the virus’ genetic material, while the E protein, they hypothesized, worked to coordinate the M proteins in this task.

Based on the results of the in silico modeling, the researchers concluded that “the M protein dimer may represent a valuable target for drugs intended to treat Covid-19 and other coronavirus diseases,” validating that suspicion by running the M protein dimer structure through a drug target identification tool and finding several high-scoring target candidates.

“My hope is that our results will provide a foundation for the development of drugs which target the SARS-CoV-2 M protein and thereby interfere with coronavirus budding,” Collins said. “I plan to contact investigators working in adjacent areas and perhaps collaborate with them so as to take further steps towards making such treatments a reality. Because of the high level of evolutionary conservation of the M protein, we anticipate that drugs targeting its function might be active against a wide array of different coronaviruses, including existing and emerging variants of SARS-CoV-2.”

To learn more about the research, read the paper: Elucidation of SARS-Cov-2 Budding Mechanisms through Molecular Dynamics Simulations of M and E Protein Complexes. The paper was published in the Journal of Physical Chemistry Letters and written by Logan Thrasher Collins, Tamer Elkholy, Shafat Mubin, David Hill, Ricky Williams, Kayode Ezike and Ankush Singhal.

To learn more about HPC in the fight against Covid-19, visit HPCwire’s timeline of supercomputing and the pandemic.