In this small article, we provide a brief introduction about the way the SARS coronavirus 2 (SARS-CoV-2) operates, and we provide results of our computations of the motion of its spike from its closed state to its open, receptor-binding state.
Introduction
The SARS coronavirus 2 (SARS-CoV-2) – the virus that causes the COVID-19 disease – has transmembrane spikes (S proteins on the image below) attached to its lipid membrane. It is because of these spikes – their relatively large number – that this type of virus is called a coronavirus. The coronavirus uses its spikes to recognize a host cell then attach to it and infect it with its viral RNA which encodes the virus instructions. This strategy is used by many viruses, including other coronaviruses, influenza viruses, and HIV. Once the viral RNA is inside the host cell, the host cell starts to produce copies of the virus based on the instructions stored in the viral RNA thus leading to virus propagation. The SARS-CoV-2 spike is considered as one of the main targets of antibodies [1].
An illustrated visualization of the SARS-CoV-2. Image credits: CDC/Alissa Eckert.
Let’s see how the spike looks like from the side view and from the top view.
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The side view of the spike (Source: PDB 6VXX): the spike is represented via its Gaussian surface (left) and via its secondary structure (right), the molecules around are sugars. The bottom part of the spike would be attached to the virus capsid. Click on an image to open its full-size version in a new window.
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The top view of the spike (Source: PDB 6VXX): the spike is represented via its Gaussian surface (left) and via its secondary structure (right), the molecules around are sugars. The bottom part of the spike would be attached to the virus capsid. Click on an image to open its full-size version in a new window.
The spike consists of glycoproteins and promotes entry into human cells by binding to a receptor molecule (see the following section).
As you can see, the spike is covered with other small molecules – these are sugar molecules. Many viruses are using sugars to defend themselves from the host immune system. This works as a disguise because many of our cells are coated with sugars and our immune system recognizes these sugars and does not attack them. But the SARS-CoV-2 does not have sugars on top of its spikes to be able to recognize the receptor molecule and bind to it. This makes the top part of the spike – the binding part – the main target of antibodies. Neutralizing antibodies bind to the top part of the spike and once the neutralizing antibodies are there, the virus can no longer recognize the receptor molecule and infiltrate the host cell, and thus it can no longer reproduce itself.
The spike of the SARS-CoV-2 is formed by three copies of the S protein which form the C3 symmetry. You can see them in the image below colored in three colors.
The top view of the spike in the closed state. Different colors designate proteins in the spike. Small molecules around the spike are sugars.
The receptor-binding domain of the SARS-CoV-2
The SARS-CoV-2 spike promotes entry into human cells by binding to a receptor molecule – an enzyme called Angiotensin-Converting Enzyme 2 (ACE2) [1, 2, 3].
The secondary structure representation of the ACE2 molecule.
The ACE2 molecule is a natural protein present on the surface of some of our cells. It is present in epithelial cells of the lungs (in the airways and alveoli) and the intestine, and in endothelial cells of the heart and the kidneys. The ACE2 molecule is vital to our body because it is for example used together with the ACE molecule to regulate blood pressure by converting angiotensin molecules. The coronavirus which caused the SARS outbreak in 2002 also binds to the same ACE2 molecule. But researchers have found that “the SARS-CoV-2 spikes were 10 to 20 times more likely to bind ACE2 on human cells than the spike from the SARS virus from 2002. This may enable SARS-CoV-2 to spread more easily from person to person than the earlier virus” [4].
One part of the SARS-CoV-2 spike protein, positioned on the top of the spike, recognizes and grabs a receptor molecule (i.e. ACE2) on the host cell membrane and another part fuses to the host cell membrane [3]. Only one out of the three spike proteins binds to the ACE2 receptor molecule at a time.
The images below show the receptor-binding domain of the SARS-CoV-2 spike in its open state bound with the human ACE2 (Source: PDB 6VW1).
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The secondary structure representation of the receptor-binding domain of the SARS-CoV-2 spike (blue) complexed with its receptor human ACE2 (white).
As you can see, the receptor-binding site of the SARS-CoV-2 spike tries to “complete” the receptor molecule, ACE2. This can be better seen from a movie below:
The SARS-CoV-2 spike in motion
Let’s see how the SARS-CoV-2 spike operates in motion.
The movies below show how the spike goes from the closed state (the down state) to the open state (the up state). The open state is the state which can recognize the ACE2 molecule, leading the virus particle to fuse with a human cell.
The side view of the spike.
The view of the spike from another angle.
The top view of the spike.
You can download the computed trajectory in different formats below (in zipped archives):
The SAMSON file integrates the structure of the spike, the open and closed conformations (double click to restore them) as well as the path computed by the ARAP module and the path post-processed by the P-NEB module (double click to start and stop animation).
Please note that these trajectories are provided as is. They have not been experimentally verified, but could serve as an illustration of the spike motion, and might be useful in further calculations. They might have to be post-processed and / or further validated before being used. All images, animations, structures and trajectories provided here are being released under the open CC BY 4.0 license.
Please email contact@oneangstrom.com for more information.
How this motion was computed
To determine this motion in SAMSON we took two known states of the spike [1]:
These two structures differ in the number of residues, which made the pipeline more complex. Thus, we performed the following pipeline:
- For both structures, 6VXX and 6VYB, we modified the bond orders in sugars using a python script and the Python scripting module. It is necessary for the next step consisting of adding hydrogens. For residues, SAMSON sets bond orders when importing.
- For both structures, 6VXX and 6VYB, we added hydrogens and performed some minimization steps.
- We used the ARAP Interpolation Path module to generate an interpolated path between these two states: as the starting conformation we set the open state (6VYB) and as the goal conformation we set the closed state (6VXX). The generation of this path took less than half a minute on a laptop. The ARAP Interpolation Path module produces the path for the structure of the starting conformation.
- Because the closed state (6VXX) and the open state (6VYB) differ in the number of residues, we took a conformation for the closed state from the path obtained with the ARAP Interpolation Path module since the path corresponds to the structure from the open state conformation and minimized it.
- We did step 3 but with this newly obtained closed state conformation as the goal conformation.
- We used the P-NEB (Parallel Nudged Elastic Band) module to improve the path obtained in step 4. The P-NEB step took about 15 minutes on a laptop.
Accessing the modules
We are making the ARAP Interpolation Path module and the P-NEB module free for everyone during the outbreak. To use them, sign up on SAMSON Connect (it’s free), download and install SAMSON (it’s free as well), and click the Add button on the modules pages.
Many other modules are free as well. If you would like to have free access to paid modules in your research against SARS-CoV-2 / COVID-19, please contact us at contact@oneangstrom.com.