How the Universal MSA52 Aptamer Recognizes the SARS-CoV-2 Spike Protein

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the COVID-19 pandemic. The prominent characteristic of SARS-CoV-2 is the use of a trimeric spike (S) glycoprotein to invade the host cell; therefore, the S protein has become a major drug and vaccine target. Recently, a universal aptamer (MSA52) has been reported to bind to the S protein of seven former variants of concern (VOCs) in both glycan and nonglycan forms. However, no molecular details regarding these interactions are currently available. Thus, in this work, molecular dynamics (MD) simulations were performed to understand the binding of MSA52 to the S protein in both its nonglycosylated (NG) and glycosylated (G) forms. In the NG, MSA52 is inserted between the receptor binding domain (RBD) and the N-terminal domain (NTD), whereas most parts of MSA52 were in contact with the RBD in the G form. This binding is observed to be driven primarily by electrostatic interactions. MSA52 seems to bind more tightly to NG than G. In G, not only protein components but also glycans interact with MSA52. MSA52 targets the RBD like other existing aptamers, but it binds to a conserved region, explaining its ability to recognize seven VOCs. Furthermore, MSA52 can bind both RBD-up and RBD-down conformations, which could be beneficial for the effective prevention of viral infection during different mechanistic stages. The molecular insights obtained here will be useful for the future design of more effective SARS-CoV-2 aptamer-based biosensors. © 2025 The Authors. Published by American Chemical Society