biostudies-literatureMonti MEuropean Research CouncilInnovationsfondenLundbeck FoundationNovo Nordisk FondenEIT Health451-464https://www.ebi.ac.uk/biostudies/studies/S-EPMC10801686biostudies-literatureUnknown128(2)It is not well understood why severe acute respiratory syndrome (SARS)-CoV-2 spreads much faster than other β-coronaviruses such as SARS-CoV and Middle East respiratory syndrome (MERS)-CoV. In a previous publication, we predicted the binding of the N-terminal domain (NTD) of SARS-CoV-2 spike to sialic acids (SAs). Here, we experimentally validate this interaction and present simulations that reveal a second possible interaction between SAs and the spike protein via a binding site located in the receptor-binding domain (RBD). The predictions from molecular-dynamics simulations and the previously-published 2D-Zernike binding-site recognition approach were validated through flow-induced dispersion analysis (FIDA)─which reveals the capability of the SARS-CoV-2 spike to bind to SA-containing (gThe journal of physical chemistry. BTwo Receptor Binding Strategy of SARS-CoV-2 Is Mediated by Both the N-Terminal and Receptor-Binding Spike Domain.PMC108016868559230211-00066BR287-2018-1836825080R303-2018-3495NNF18OC0032628Monti MDi Rienzo LMiotto MOtzen DESomavarapu AKBaranov MVGolbek TWGosti GFrans MTTartaglia GGRoeters SJWeidner TRuocco Gvan den Bogaart GBoltje TJRossing ENagaraj MMilanetti EMoons SJfalseTwo Receptor Binding Strategy of SARS-CoV-2 Is Mediated by Both the N-Terminal and Receptor-Binding Spike Domain.It is not well understood why severe acute respiratory syndrome (SARS)-CoV-2 spreads much faster than other β-coronaviruses such as SARS-CoV and Middle East respiratory syndrome (MERS)-CoV. In a previous publication, we predicted the binding of the N-terminal domain (NTD) of SARS-CoV-2 spike to sialic acids (SAs). Here, we experimentally validate this interaction and present simulations that reveal a second possible interaction between SAs and the spike protein via a binding site located in the receptor-binding domain (RBD). The predictions from molecular-dynamics simulations and the previously-published 2D-Zernike binding-site recognition approach were validated through flow-induced dispersion analysis (FIDA)─which reveals the capability of the SARS-CoV-2 spike to bind to SA-containing (g2024-01-01T00:00:00Z2024 Jan2026-05-29T09:46:45.978Z2025-04-04T21:16:34.537ZS-EPMC108016863819065110.1021/acs.jpcb.3c06258