SARS-CoV-2: its infectivity and ductility are an open door to new treatments

Ductile regions of proteins influence infectivity

Some structural elements of proteins escape the experimental procedures of crystallography and X-ray diffraction. But they are still important, on the contrary, they are often crucial for their functioning. That lack of structure is a useful feature.

Ductile regions (IDRs) are biologically active and highly dynamic in molecular recognition, in binding with other biomolecules or atoms (DNA, RNA, proteins, sugars, metals) and in the assembly of molecular complexes. They can rapidly adopt interconvertible conformations under different physiological conditions. Thus, structured and flexible elements complement each other.

Viral proteins contain a large number of ductile regions and various studies correlate this characteristic with virulence. In SARS-CoV-2, as in all viruses, ductile regions establish interactions with other proteins and with genetic material. For example, in the N nucleoprotein, its high proportion of flexible regions allows a close interaction with the viral RNA and with other membrane proteins, such as the M glycoprotein, which is the most abundant in the virus, or with the proteins of the virus. host cell, thus being multifunctional.

The rest of the SARS-CoV-2 proteins, including protein S, have a moderate or low content of ductile regions, but some of them can be crucial to modulate the infection. In a recent work published in Nature, up to three hundred and thirty-two interactions have been found between SARS-CoV-2 proteins and human proteins. Most of them feature protein S and non-structural accessory proteins Nsp7 and Nsp8 of the virus. The flexibility and movement of the S proteins in the capsid shell (they are counted up to about forty units) is decisive for the recognition of cell membranes and their binding to them. In several works, with the help of high-resolution electron cryomicroscopy, it has been proven that there is a continuous and characteristic flexibility in protein S, which is what makes this virus different from other coronaviruses.

As has been suggested, the ductile regions of the ‘SARS-CoV-2 dark proteome’ are also relevant. Computational and computer tools provide valuable information on whether or not a protein adopts a well-defined three-dimensional structure, and whether or not a flexible region is involved in molecular recognition. The recent study published in Cellular and Molecular Life Sciences concludes that almost all SARS-CoV-2 proteins have one or more molecular recognition segments. Increased flexibility in specific regions of proteins correlates with infectivity. In some cases, the predictions associated with these correlations become tested.

A recent work published in Nature shows clinical evidence that the D614G mutation in the SARS-CoV-2 protein S, detected in a variant that emerged in Europe during the month of January, increases replication in the epithelial cells of the lung and in the primary tissues of the respiratory tract, thereby enhancing infectivity. This mutation – a substitution of aspartate for glycine – entails a loss of complexity in the sequence and a gain in local flexibility. A strong phenotypic change related to virulence and associated with a glycine mutation has also been described in the bacterium Mycobacterium tuberculosis.

The relationship between ductility and infectivity is being useful in the design of new therapies aimed at blocking the entry of the virus into the cell or its replication. Some of the designs for vaccines and antiviral drugs attempt to block specific sites on proteins inspired by this knowledge to prevent infection. It is an open door to hope.

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