How do their mutations change their biology?

The Indian variant, which has been circulating in India for a few weeks, carries several mutations in its S protein: How do these affect the interactions with the ACE2 cell receptor or neutralizing antibodies? A previously published study provides the first answers.

India is the second most Covid-19 affected country in the world with 17.3 million confirmed cases, ahead of Brazil and behind the United States. In the last few weeks theepidemic to get out of control. The number of cases is increasing exponentially, as is the number of deaths. 350,000 new infections were confirmed for April 25, 2021 alone. Several countries including France, Great Britain and the United States have pledged to support the country. In the capital New Delhi, the detention is extended by a week.

Is this unprecedented surge in the epidemic with the spread of the Indian variant of SARS-CoV-2 ? There is currently no known cause-and-effect relationship. The mutations he door, and which are already known, give it a certain evolutionary advantage which favors its spread. Three of these, L452R, E484Q and P681R, are the subject ofpublished a small study on the server bioRxiv by scientists from the National Institute of Virology in Pune. Thanks to them Crystallography, they could see the interactions between protein S of the Indian variant and the ACE2 receptor.

A stronger connection with ACE2 …

The mutations L452R and E484Q are in the Receptor binding domain (RBD) of Protein S, the region that physically interacts with ACE2. For variants without an L452R mutation, the Leucine (L) forms a pocket with two other neighboring amino acids hydrophobic on the surface of the RBD. In the Indian variant, leucine is represented by a. replaced Arginine (R) that is not hydrophobic. The hydrophobic pocket is therefore broken. According to calculations by scientists, the formation of the Indian ACE mutant complex requires lessenergy (-94543.180 kcal / mol) compared to the non-mutated strain (-93732.305 kcal / mol).

L ‘Glutamic acid binds at position 484 of the S protein (E484) electrostatic with a remainder of the ACE2 receptor. Replaced by a Glutamine in the Indian variant (E484Q) this bond no longer exists. Scientists believe that the RBD-ACE2 complex is more stable in the Indian variant, especially because of the disappearance of the hydrophobic pocket.

Another mutation, P681R, is not in the RBD, but in the effective range of furin, a Protease which cuts on a chain of basic amino acids. In the Indian variant is the proline (P) is replaced by an arginine (R), which is exactly one of the amino acids recognized by furin. The action of the latter is essential to separate the two Subunits of Protein S and start the merger Virus with the host cell membrane. The P681R mutation could therefore, according to scientists, increase the speed of membrane fusion and internalization of the virus and automatically increase its transmissibility.

… and with weakened antibodies

Indian scientists have also observed changes in the interaction between the Indian mutant and an antibody monoclonal Neutralizing agent (REGN10933). As observed with other variants, the E484Q mutation prevents the formation of a Hydrogen compound between protein S and the heavy chain of the antibody. The L452R mutation also deprives the antibody of a site of attachment to the virus, this time a hydrophobic interaction. Combined, these two mutations would reduce the effectiveness of neutralizing antibodies.

Currently, the Indian variant B.1617 is not considered a Variant of Concern (VOC) like the English, Brazilian or South African variant, but as a Variant of Interest (VOI). One variant of interest has mutations that modify their binding to the receptor, reduce the effect of neutralizing antibodies and make diagnosis more difficult. When scientists prove it actually is more contagious and more lethal, then it’s likely viewed as a variant of the worry.

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