RNA polymerase of sars cov2 with remdesivir
The genetic code is based on four letters (that means four chemically different Molecules with code letters A, U, G and C in the case of RNA). In making a new (negative-)identical strand copy there is the selection rule: A pairs only to U, G only to C; only this pairing guarantees the validity of information in the copy. The example shown here: a stretch of RNA within the cov2-polymerase. All bases of the new strand (red) are paired to the template strand (blue) . Demonstrated are here an A-U pair (to the left) and a G-C pair . The pairs don't engage in true chemical bonding, because later the strands have to be separated easily. Therefore here are less strong hydrogen bridge bonds (the hydrogen atoms involved can't be located in this investigation method). Within A-U there are two bonds, in G-C there are three. That is the only difference for the selection of the next base. No wonder there is a mistake every 100 000th position.
The RNA polymerase may be cheated. If you offer besides the natural bases A, U, G and C molecules with similar shape and known pairing properties, these stranglings are also incorporated. Remdesivir is a molecule similar to A. It may be incorporated instead of A , it pairs to the U opposite . The poisenous part of remdesivir is a cyano group , which is absent in A.
Back to the with the RNA strands. If the remdesivir molecule is incorporated, the polymerase works on for another three positions . With every step the polymerase has to advance one step to the right along the template strand (blue) to incorporate the next base; the RNA double strand produced is pressed out of the polymerase to the left. The polymerase has a tight grip on the double strand to keep it in position. There is a specially tight spot . The cyano group protruding from remdesivir gets cought in this place and thus prevents a new positioning of the polymerase for the next step . The blocking amino acid (Ser861) is bound in a rigid helix and can't avoid the cyano group of remdesivir.
this demonstration.
Literature:
G Kokic et al, Nature Communications 12, 279 (2021), DOI 10.1038/s41467-020-20542-0