Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19 disease, has caused millions of deaths worldwide since it started spreading at the end of 2019. SARS-CoV-2 is an enveloped virus, whose spherical lipid bilayer is studded with multiple copies of a homotrimeric class I fusion glycoprotein, the spike (S). This molecular machinery, cloaked in a glycan shield of 22 N-linked and at least 2 O-linked glycans per protomer, is used by SARS-CoV-2 to gain access to the cytoplasm of the human cells upon latching onto a specific molecular target exposed on the host cell, the angiotensin-converting enzyme 2 (ACE-2). The deposition of the first cryo-EM structure of the SARS-CoV-2 S protein in mid-February 2020 marked the beginning of our endeavor to fight COVID-19 using high-performance computing (HPC). In this talk, I will present how we deployed <i>in-silico</i> modeling and all-atom molecular dynamics simulations in order to unveil functional and dynamical properties of the SARS-CoV-2 S protein at different spatial scales and in the context of viral infection. This entails the building and the simulations of the full-length, fully-glycosylated model of the SARS-CoV-2 S protein, of the full-length, fully-glycosylated human ACE-2 receptor, and of the composite, two-parallel-membrane model of the ACE-2/spike encounter complex occurring before infection. Finally, our team effort culminated with the building of the entire SARS-CoV-2 viral envelope that will usher in new opportunities to investigate viral infection through HPC at subcellular scales. Overall, our contribution significantly advanced the understanding of the SARS-CoV-2 virus, and also inspired the creation of an international sharing hub for COVID-19-related simulation data. This allowed thousands of scientists from all over the world to delve more into the intricacies of the spike and to use our simulations (and those of others) for vaccine design and drug development purposes.

Multiscale modeling and simulations of the SARS-CoV-2 spike protein

ACS Fall 2021

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