Biological and Medicinal Chemistry

SARS-CoV-2 and MERS-CoV spike protein binding studies support stable mimic of bound 9-O-acetylated sialic acids

Authors

Abstract

Many disease-causing viruses target sialic acids (Sias), a class of nine-carbon sugars known to coat the surface of many cells including those in the lungs. Human beta coronaviradae, known for causing respiratory tract diseases, often bind Sias, some preferentially bind 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 Sias has been reported and its preference towards α2-3-linked Neu5Ac shown. Nevertheless, O-acetylated Sias-protein binding studies are difficult, due to the ester lability. We studied the binding free energy differences between Neu5,9Ac2α2-3GalβpNP and its more stable 9-NAc mimics binding to SARS-CoV-2 spike protein using molecular dynamics and alchemical free energy simulations. We identified multiple Sias-binding pockets, including two novel sites, with similar binding affinities to those of MERS-CoV, a known co-binder of sialic acid. In our binding poses, 9-NAc and 9-OAc Sias bind similarly, suggesting an experimentally reasonable mimic to probe viral mechanisms.

Content

Thumbnail image of manuscript-mers-sarscov2.pdf

Supplementary material

Thumbnail image of manuscript-mers-sarscov2_SI.pdf
Supplementary Information for SARS-CoV-2 and MERS-CoV spike protein binding studies support stable mimic of bound 9-O-acetylated sialic acids
Supplementary Information for SARS-CoV-2 and MERS-CoV spike protein binding studies support stable mimic of bound 9-O-acetylated sialic acids: Conformational change of the SARS-CoV-2 S protein images, MM-PBSA results and energy decomposition analysis for SARS-CoV-2 and MERS-CoV S proteins, fully SOMD results for Sia-SARS-CoV-2 S protein binding, diagram of a thermodynamic cycle to estimate binding free energies, example overlap matrices to analyze the quality of SOMD results, and simulation-ready parameter files for the pNP residue in AMBER.
Thumbnail image of mers-sarscov2_SI_vid.mp4
Overlay of example MD simulations of Sia unbinding and binding events in the SARS-CoV-2 S protein (6VSB)
Overlay of example MD simulations of Sia unbinding and binding events in the SARS-CoV-2 S protein (6VSB) with interacting arginines represented with green VDW, Sia represented with large VDW, and S proteins in NewCartoon representation and colored by index.