Why do newer variants of SARS-CoV-2 spread more easily?

The mutable nature of viruses is rooted in the randomness inherent in the process of making copies of any object, which makes mistakes inevitable. When host cells make copies of SARS-CoV-2, errors occur, called mutations. The vast majority of viruses do not survive replication errors. But some do, and may even thrive as a result of the changes, supplanting ancestral viruses and spreading more efficiently through their host population. Some parts of the virus structure are more resistant to mutations: the spike protein is the most tolerant of changes. Mutated viruses that survive and develop are called variants. These began to emerge in earnest from SARS-CoV-2 in November 2020, with the emergence of the Alpha variant and its subsequent detection in Kent, in the south-east of England. The newer variants must have some advantage over the old ones if they are to become the dominant form of the virus. This benefit could be achieved in a number of ways, but for a respiratory disease like covid-19, one of the most important factors is transmissibility, the ease with which the virus passes from person to person.

One of the first mutations to increase transmissibility was called N501Y, sometimes known as “Nelly”, one of the eight mutations that characterized the spike protein of the Alpha variant. The technical name for the mutation is relatively straightforward once you understand that it refers to changes in the virus’s genome, and the amino acid structure it codes for. The “501” means that the change occurs at the 501st amino acid in a chain of 1,273 that make up the peak. The order and composition of these amino acids is dictated by a corresponding genomic sequence, so “501” refers to both the position on the genome and the position on the amino acid chain. “N” is the abbreviation for asparagine, which in N501Y is replaced by “Y”, which is tyrosine. Since different amino acids have slightly different chemical properties, this exchange impacts the structure of the spike protein. As a result, the way the electric charge is distributed across it changes. This slightly changes the shape of the protein because areas of positive electric charge attract areas of negative charge. With this dynamic, the N501Y allows a crucial part of the tip to twist approximately 20 degrees, allowing it to find a tighter fit with the ACE2 receiver. Better binding occurs as a result, which means that any copy of the variant that enters the body is more likely to find its target and start to replicate. This increases the transmissibility. Other mutations perform a similar trick, releasing different parts of the tip in different ways so that it can bind to ACE2 more effectively.

Changing the shape of the peak is not the only way to increase transmissibility. Delta, the variant that was first detected in India and is now spreading around the world, appears to be even more transmissible than Alpha and the other variants. Completely why is not clear, as detailed structural studies of Delta Point have not yet been completed. But Ravindra Gupta, a molecular virologist at the University of Cambridge, and colleagues argue that the increased transmissibility of Delta is due, in part, to a mutation at site 681. This is the point on the peak where, after having bound to ACE2, the protein is split in half. Dr Gupta says that P681R, aided by two shape-altering mutations elsewhere, makes it easier to cut the protein and thus get it into cells. Its presence also means that once a cell starts producing particles, their spike proteins can reach the precut surface of the cell. This can lead to virus particles that are stripped of the parts that the antibodies recognize and ready to fuse with any neighboring cell. It can also encourage infected cells to group together with others.