Comparative molecular dynamics analysis of SARS-CoV-2 RBD interactions with heparin oligosaccharides tethered to a U-shaped DNA origami scaffold

Abstract COVID-19 remains a global health threat due to its rapid transmission and the emergence of new variants. Despite advances in vaccines and antiviral treatments, there remains a pressing need for alternative strategies that prevent viral entry at the earliest stage. Heparin, recognized for its electrostatic affinity toward the SARS-CoV-2 spike protein, has demonstrated potential in disrupting viral attachment. In response to this challenge, the present study proposes a modeled DNA origami–linker–heparin construct that integrates a DNA origami U-shaped cage with heparin through a spermidine-based linker, designed to investigate the structural and energetic behavior of tethered heparin chains in the presence of the SARS-CoV-2 receptor-binding domain (RBD). Three hybrid complexes with varying heparin lengths were designed and evaluated using all-atom molecular dynamics simulations at 300, 310, and 320 K, with 320 K considered an elevated-temperature stress condition. The findings indicate that the complex containing decasaccharide heparin exhibits the most stable structure and the strongest interaction with the RBD, as evidenced by consistently lower electrostatic and van der Waals energies. Moreover, post-MD molecular mechanics/Poisson–Boltzmann surface area calculations provided relative binding-energy estimates and revealed the energetic contributions of molecular-mechanics, polar-solvation, and nonpolar-solvation terms. These results suggest that the predicted interaction stability of the tethered heparin–RBD complexes arises from the combined effects of electrostatic interactions, solvation contributions, and persistent intermolecular contacts. Overall, the results provide a comparative structural and energetic characterization of three tethered heparin systems and identify the decasaccharide-containing construct as having the most favorable relative interaction energetics among the modeled systems. Experimental validation and matched control simulations will be required to determine biological relevance and any scaffold-dependent advantage.