In brief

When SARS-CoV-2's spike protein interacts with the human ACE2 receptor, the dissociation of its S1 and S2 subunits triggers the fusion of viral and host membranes.

© Firdaus Samsudin

Secrets of the spike protein, revealed

22 Sep 2021

Tracking how SARS-CoV-2 interacts with host cell receptors during infections may give us new ideas for COVID-19 drug targets.

Since the emergence of COVID-19 nearly two years ago, researchers have raced to discover the coronavirus’ modus operandi. Similar to a choreographed dance, SARS-CoV-2 infections involve an intricate series of dynamic molecular events beginning with the virus binding to a host receptor called ACE2, aided by club-shaped ‘spikes’ that dot the pathogen’s surface.

However, until now, scientists have only captured snapshots of this molecular dance, such as the cleaving of the spike (S) protein into subunits called S1 and S2 after latching onto ACE2. To help design better clinical strategies for resisting COVID-19, experts are now seeking a more comprehensive, high-resolution view of how these early events mobilize viral entry into cells.

Bridging this knowledge gap is Peter Bond, a Senior Principal Investigator in A*STAR’s Bioinformatics Institute (BII). Along with his collaborators, Bond leveraged a powerful combination of two complementary technologies to map structural changes occurring in the S protein during initial infection.

“Amide hydrogen/deuterium exchange mass spectrometry enabled characterization of the changes of dynamics of S protein upon ACE2 binding, while our molecular dynamics simulations elucidated corresponding atomic-level motions,” explained Bond.

The team’s study yielded some unexpected findings. For example, the attachment of ACE2 to the S protein triggered distinct structural changes in two ‘hotspots’ located some distance away from the binding site. They also observed more intense activity in the regions around the S1/S2 cleavage site, which Bond suggests could be a priming step before enzymes enter to proteolyze the S protein at remaining uncleaved sites, including the nearby S2’ site. Meanwhile, the coronavirus’ stalk region—a structure that anchors the spike to the viral envelope—stiffened and stabilized after ACE2 binding.

Collectively, these observations indicate that interactions between the S protein and ACE2 aren’t simply a means for the coronavirus to recognize which cells to infect. These interactions may also have a far-reaching influence on other downstream processes critical to viral entry and infection, including the cleavage and fusion of the S protein.

“In addition, the proteolytic sites in the S protein are both known to be parts to which some neutralizing antibodies bind,” commented Bond, making these hotspots prime targets for potential therapeutic development.

The newly-identified infection dynamics may also help expand our understanding of SARS-CoV-2 variants, with Bond noting that the Alpha and Delta SARS-CoV-2 variants harbor mutations near the S1/S2 cleavage site. In follow-up studies, the researchers plan to use a similar approach to uncover how mutations in these hotspots make some variants more of a threat.

The A*STAR-affiliated researchers contributing to this research are from the Bioinformatics Institute (BII).

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Raghuvamsi, P.V., Tulsian, N.K., Samsudin, F., Qian, X., Purushotorman, K., et al. SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets. eLife 10, e63646 (2021) | article

About the Researcher

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Peter J. Bond

Senior Principal Investigator

Bioinformatics Institute (BII)
Peter J. Bond is a Senior Principal Investigator at the Multiscale Simulation, Modelling and Design (MSMD) group at A*STAR’s Bioinformatics Institute. His group develops computational models to resolve the dynamics of biomolecules over multiple time and length scales, focusing particularly on mechanisms of infectious disease, the host immune response to bacterial and viral pathogens and therapeutic intervention strategies.

This article was made for A*STAR Research by Wildtype Media Group