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Tuesday, January 25, 2022

Equilibrium simulation of SARS-CoV-2 spike protein highlights its global conformational characteristics

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to impact nearly every aspect of human life around the world. SARS-CoV-2 is a member of the beta coronavirus genus, as are SARS-CoV and MERS-CoV, which were responsible for the 2003 SARS outbreak and the 2012 Middle East respiratory syndrome respectively.

Study: Post-Translational Modifications Optimize the Ability of SARS-CoV-2 Spike for Effective Interaction with Host Cell Receptors. Image Credit: Dotted Yeti/Shutterstock

The binding of the extended spike glycoproteins on the viral envelope to specific human cell surface receptors is the first step in viral entry and infection in SARS-CoV-2 and other coronaviruses in general. These envelope spike proteins contain all of the components required for human cell infection; after binding to the surface receptors, they initiate the fusion of the ten viral and human membranes, then release the viral genome into the host cell.

Many SARS-CoV-2 spike cryo-EM structures have been resolved recently due to major efforts to characterize the structural properties of the spike. Although the resolved structures provide crucial information on the structural details of the globular spike domain (spike head), which contains the receptor-binding domain (RBD) that recognizes and binds to the angiotensin-converting enzyme 2 (ACE2) host cell receptors, the full spike still lacks several functionally important regions.

The highly conserved fusion-peptide segment, which initiates the fusion of the viral and host cell membranes, the stalk heptad repeat 2 (HR2) domain, which undergoes refolding during membrane fusion, and the transmembrane (TM) domain, which contains multiple palmitoylation sites and is thus required for assembly and activity in other viruses, are among them.

A team of researchers set out to build a full-length, membrane-embedded spike to study its conformational dynamics at the atomic level using molecular dynamics (MD) simulations to understand better how this important component of the virus machinery works.

A preprint version of the study is available on the bioRxiv* server while the article undergoes peer review.

The study

To construct the missing areas in the spike head and stalk, including the HR2 domain, the authors used homology modeling with several template structures from homologous coronaviruses, including SARS-CoV and MERS-CoV, as well as fragment-based, ab initio modeling, and secondary structure prediction.

In addition, the authors performed an extensive procedure for constructing a stable model of the TM domain, in which sequence-based secondary structure prediction for the TM region was combined with protein-protein docking for generating the initial configurations of TM trimers, followed by MD relaxation of suitable TM trimeric configurations in the membrane.

The researchers defined the spike’s global motions in terms of spike head movements relative to the stalk region during simulations to better understand the dynamics used by the spike to sample the packed cellular surfaces. Head-twist and head-bend angles and head distances measured individually with respect to the spike neck, HR2 domain, and TM domain were used to quantify these motions.

The spike can sample enormous head twist angles for both the HR2 and TM domains in its fully glycosylated, native state, illustrating the substantial conformational flexibility accessible along this degree of freedom. Concerning the HR2 domain, a wide normal distribution of head-twist angles is found, with the highest recorded configurations turned by over 90˚ relative to the beginning structure.

Spike-head can sample conformations that are practically oppositely facing (turned by as much as 160°) relative to the beginning orientation in the TM domain, despite being sparsely populated. Around the spike neck, a smaller range of motion is allowed, with the most populous regions being close to the beginning structure.

The length of the linkers connecting the different spike domains can be directly related to these outcomes. When compared to the domain around which the spike head displays relatively more restricted motions (spike neck), which is connected to the spike head by a smaller linker, the domains around which the spike head displays larger motions (HR2 and 350 TM domains) are connected by longer linkers (linker 2: 13 residues; linker 3: 11 residues) (linker 1: 7 residues).

Furthermore, a direct comparison of the head-twist motions in the glycosylated form to the control non-glycosylated system reveals that these motions become constrained in the latter, particularly around the HR2 and TM domains. These findings suggest that glycans play an unexpectedly important role in the spike’s overall dynamics.


SARS-CoV-2’s spike protein is a key component of the virus’s infection and, as a result, is a primary target for diagnostics and vaccines developed to combat the virus’s disease. It is critical to characterize the spike’s structure and behavior in the greatest detail and under the most realistic settings possible to better understand the multiple mechanical pathways in which it is involved.

The authors presented a full model for the full-length spike in its native, glycosylated and palmitoylated, membrane-bound form, which was used for several microseconds of atomistic simulations to highlight some of the dynamics used by the spike to search for and locate host cell receptors effectively.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.


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