Coronaviruses are enveloped RNA viruses that are distinguished by the numerous spike proteins projecting from their surfaces. While a number of examples are known, the most recent example, SARS-CoV-2, is especially well known for being the causative agent of COVID-19 and of the 2020 pandemic. The viral lifecycle, including cellular entry, replication, assembly, and release opens up multiple avenues for investigation suitable for molecular dynamics simulation, a few of which are described below.

Main protease

Many of the coronavirus proteins are synthesized together as a polyprotein, which is then cleaved at specific sites by viral proteases. One of these is the main protease (Mpro). The active site of Mpro includes a number of histidine residues, which can adopt one of multiple protonation states, normally unresolved by crystallography. We used molecular dynamics simulations to sample 12 different permutations of protonation states, judging them by the resulting stability of the protein and of the active site in particular.

(left) Mpro dimer. (right) The catalytic dyad Cys145/His41 forms the core of the active site.

Spike conformational change

Before infection can take place, the receptor binding domain (RBD) on the spike protein must become accessible. The ease with which this closed-to-open transition takes place may determine in part how infectious the virus is. Free-energy calculations on the nation’s fastest supercomputer, Summit, will reveal the transition pathway as well as the energetics along it.

Spike-protein trimer in closed (left) and open (right) states. The accessible RBD is boxed on the right.

RBD-ACE2 interaction

After opening, the RBD binds to ACE2, a membrane protein on the surface of some human cells, notably lung alveolar epithelial cells. This happens to be the same binding site as that used SARS-CoV, a closely related virus that caused outbreaks in 2003. Machine-learning approaches applied to long trajectories of SARS-CoV-2 and SARS-CoV RBDs bound to ACE2 were used to identify which residues contribute to differences in binding. See here for the code used to do the analysis.

Importance of amino acids in differentiating between SARS-CoV and SARS-CoV-2 RBD binding to ACE2.

Recorded talk at UIUC (Nov. 2020)