COVID-19 research — Simmerling Lab

Simmerling lab research on COVID-19

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This site is not meant to be a medical resource for COVID-19 or illnesses caused by coronaviruses. Please refer to The Centers for Disease Control and Prevention (CDC ) site.

Coronaviruses have spike glycoproteins decorating their surface; the virus uses the spikes to gain entry into host cells. Experiments have revealed the structure of the spike before and after viral entry, and dramatic changes take place. We aim to understand the full details of these conformational changes, including understanding what triggers the process, each of the steps that occurs along the way, and whether interfering with this structural change could provide an avenue for blocking coronaviruses from infecting host cells.

Spike complex — We are modeling the “spike” (a trimer made of the red, yellow, and blue proteins on the upper left) on the coronavirus. The spike binds to the human ACE2 receptor protein (pink proteins, bottom) on the surface of cells that line the human respiratory system.

This image is a cartoon of the process by which a coronavirus infects a host cell. The spike in blue/orange at the top left is attached to the surface of the coronavirus (top row of tan blocks). The orange ovals on the spike open and close, looking for the host receptor (gray) which is attached to the host cell membrane (bottom row of tan blocks). Once they bind, the spike sheds the receptor binding domains and undergoes a dramatic conformational change to attach itself to the host membrane, bridging the virus and host membranes by inserting fusion peptides into the host membrane (dark blue). The spike then undergoes a “jackknife” change and pulls the virus and host cell membranes together, leading to merging of the membranes (far right) and entry of the virus into the host cell. Blocking this process stops infection.

Our all-atom simulations of the SARS-CoV-2 spike include the full spike ectodomain, with glycans, 400,000 water molecules and 200 mM NaCl, with 1.4 million atoms total.

covid.gif.gif — Modeling the dynamic motions of the coronavirus spike

Our simulations aim to understand the range of motions undergone by the spike as it searches for the host cell, and then undergoes a series of changes to enact cell fusion. This movie shows one aspect of these changes, as the receptor binding domain of the spike undergoes opening and closing motion. If researchers understand more about these motions, they may be able to design molecules that bind to the spike and interfere with the motions, and thus block entry of the virus into the host cell.

The receptor binding domain (RBD) of the spike samples multiple conformations in a compromise between evading immune recognition and searching for the host-cell surface receptor. Using atomistic simulations of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we mapped the free energy landscape for RBD opening and identified interactions in an allosteric pocket that influence RBD dynamics. The results provide an explanation for experimental observation of increased antibody binding for a clinical variant with a substitution in this pocket. Our results also suggest the possibility of allosteric targeting of the RBD equilibrium to favor open states via binding of small molecules to the hinge pocket.

This work was published in the Journal of the American Chemical Society (Fallon et al, JACS 2021)

Additional videos and presentations are available here

Financial and computational support for our COVID-19 research efforts

We have received additional support as part of a joint project with DOE labs on COVID-19, “Molecular design and analysis to inform therapeutics related to COVID-19”.

The Lab received a grant for our COVID-19 project via the 2019-20 SUNY Research Seed Grant Program. Thank you SUNY Office of Research and Economic Development!

We are grateful for the award of supercomputer time from the COVID-19 HPC Consortium for our project titled “Artificial intelligence driven integrative biology for accelerating therapeutic discovery against SARS-CoV-2” (project MCB200069)

We received funding from the Stony Brook University Office of the Vice President for Research (OVPR) and The Institute for Engineering-Driven Medicine (IEDM) as seed grant funding for our project “Multiscale molecular simulations to develop inhibitors of the SARS-CoV-2 coronavirus membrane fusion protein”. Thank you OVPR/IEDM!