Analysis of the binding affinity of SARS-CoV-2 spike RBD to novel DNA origami-heparin nanostructures: a steered molecular dynamics (SMD) study

In recent years, the development of novel therapeutic strategies to inhibit emerging viruses has become a major challenge in pharmaceutical research. This study aimed to design innovative nanostructures to prevent the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein from interacting with host cells. DNA origami and heparin molecules were incorporated into various nanocomplexes, consisting of a U-shaped DNA origami cage, heparins of different lengths (tetrasaccharide, hexasaccharide, decasaccharide), and a spermidine-functionalized linker positioned near the viral RBD. Molecular dynamics (MD) simulations, complemented by steered MD (SMD) simulations, were performed to evaluate stability and quantify the forces required to detach the RBD. The SMD results reveal strong electrostatic and van der Waals interactions that effectively prevent RBD dissociation. Furthermore, MM/GBSA calculations show negative binding free energies (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mrow><mml:mtext>ΔG</mml:mtext></mml:mrow><mml:mrow><mml:mtext>bind</mml:mtext></mml:mrow></mml:msub></mml:mrow></mml:math> ranging from - 36.9 ± 7.9 kJ/mol for tetrasaccharide to - 170.9 ± 14.0 kJ/mol for decasaccharide), confirming that longer heparin chains enhance binding affinity and complex stability. These findings underscore the computationally promising potential of these nanostructures for inhibiting viral attachment to the ACE2 receptor. The calculated binding affinity and pulling work further confirm the computationally observed affinity of these nanocomplexes for the RBD. While these computational findings indicate high binding affinity and inhibitory potential, further studies are required to evaluate biocompatibility, stability in biological fluids, immunogenicity, and suitable delivery methods for these nanostructures. This study provides a structural modeling framework integrating DNA origami, heparin, and SMD-MM/GBSA analyses, highlighting the potential of these nanostructures for SARS-CoV-2 inhibition and antiviral therapeutic development.