Magazine - Summer 2021



Tell us more about the research under the White House’s COVID-19 High-Performance Computing Consortium.

protein, one M protein, and no proteins (see below).

Logan: When I joined Conduit, the COVID-19 pandemic had just begun and I wanted to do something to help. I did not know much about molecular dynamics simulations or coronaviruses, but I taught myself a lot of information quickly. My previous research experiences in synthetic biology and neuroscience had prepared me to rapidly absorb the necessary panel of knowledge. After just a few weeks of intensive literature research, I suggested leveraging the computational background of Conduit’s team to study a part of the SARS-CoV- 2 life cycle called budding. With some input from Ricky Williams, one of Conduit’s top software engineers, I wrote a formal proposal on using molecular dynamics simulations to investigate coronavirus budding. I soon submitted my proposal to the COVID-19 High-Performance Computing Consortium, where a committee of senior scientists reviewed and accepted my project. The consortium is a U.S. government initiative which has brought together supercomputer resources from academia and industry to help fight the COVID-19 pandemic. We were awarded time and resources on the supercomputer Frontera, which is currently the 9th most powerful supercomputer in the world. I have said that we are studying SARS-CoV-2 budding using atomistic molecular dynamics simulations. I will now explain what that all means. When SARS-CoV-2 infects a cell, it first replicates its genetic material (called RNA). To finish building more of itself, the virus must then package its RNA inside of a protective spherical membrane, a process known as budding. In order for budding to occur, the coronavirus must steal a part of the membrane of a cellular organelle called the ERGIC. The coronavirus carries out budding by inducing curvature in the ERGIC membrane, which eventually leads to the formation of a bubble that encapsulates the RNA genome.

We ran our molecular dynamics simulations of these systems on Frontera over several months. Our most interesting results were in the 4M system, where the M proteins worked together to introduce a dramatic level of curvature into the membrane (see below). By contrast, the E proteins seem to keep the membrane relatively flat. Based on our results, we suggest that the M proteins might be a good target medicines to treat COVID-19. If one could design medicines which get in the way of the interactions between these M proteins, one could prevent budding and keep SARS-CoV-2 from making more of itself. Furthermore, M proteins are known to be similar across different types of coronaviruses, so such medicines might be able to combat other coronavirus diseases as well.

But how does the virus induce curvature?

It is known from experiments that two proteins, the M protein and the E protein, are sufficient to facilitate budding. However, the mechanisms behind how these proteins function in budding are poorly understood. Our molecular dynamics simulations are helping us to understand how the M protein and E protein contribute to the curvature of SARS-CoV-2 budding. Molecular dynamics is a type of computational model which allows us to visualize how molecules of interest move over time. We start with the positions of all of the atoms in our system, calculate the forces the atoms exert on each other, update their positions, and repeat. This creates a movie of molecules wiggling around and interacting. To study SARS-CoV-2 budding, we created six patches of virtual ERGIC membrane which respectively contained four E proteins, four M proteins, three M proteins and one E protein, one E

Here is a link to the preprint of "Understanding SARS-CoV-2 budding through molecular dynamics simulations of M and E protein complexes".

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