Many disease-causing viruses target sialic acids which are known to coat the surface of many cells in the host, especially in the lungs. A number of human beta coronaviradae, known for causing respiratory tract diseases, bind to sialic acids, some preferentially to those with 9-O-Ac- modification. Currently, co-binding of SARS-CoV-2, a beta coronavirus responsible for the COVID-19 pandemic, to human sialic acids is suspected but specific binding pockets are not confirmed. Additionally, O-acetylated sialic acid-protein binding studies are experimentally difficult, due to the ester lability. Chemically similar N-acetylated sialic acids are experimentally more stable and are reasonable mimics. We have used a combination of molecular dynamics and alchemical free energy simulations to study the relative binding free energy differences between 9-O-Ac and 9-NAc sialic acids in a range of potential binding pockets on the SARS-CoV-2 Spike protein, giving insight into potential binding domains and how similar the 9-NAc sialic acid mimic may be to 9-O-Ac counterparts in experimental binding studies.

Simulation studies of SARS-CoV-2 spike protein binding to sialic acids using alchemical free energy simulations

ACS Spring 2022

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