SpikeScape: A Tool for Analyzing Structural Diversity in Experimental Structures of the SARS-CoV-2 Spike Glycoprotein.

In this application note, we describe a tool which we developed to help structural biologists who study the SARS-CoV-2 spike glycoprotein. There are more than 500 structures of this protein available in the Protein Data Bank. These structures are available in different flavors: wild type spike, different variants, 2P substitutions, structures with bound antibodies, structures with Receptor Binding Domains (RBD) in closed or open conformation, etc. Understanding differences between these structures could provide insight into how the spike structure changes in different variants or upon interaction with different molecules such as receptors or antibodies. However, inconsistencies among deposited structures, such as different chain or sequence numbering, hamper a straightforward comparison of all structures. The tool described in this note fixes those chain inconsistencies and calculates the distribution of the requested distance between any two atoms across all SARS-CoV-2 spike structures available in the Protein Data Bank (excluding PDB files with only spike fragments such as the RBD), with the option to filter by various selections. The tool provides a histogram and cumulative frequency of the calculated distribution, as the ability to download the results and corresponding PDB IDs.

Free Energy Landscapes from SARS-CoV-2 Spike Glycoprotein Simulations Suggest that RBD Opening Can Be Modulated via Interactions in an Allosteric Pocket.

The SARS-CoV-2 coronavirus is an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell and is the primary target of neutralizing antibodies. 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 map the free energy landscape for RBD opening and identify 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. In addition to potential value as experimental probes to quantify RBD conformational heterogeneity, small molecules that modulate the RBD equilibrium could help explore the relationship between RBD opening and S1 shedding.