AbstractSolid core nanoparticles coated with sulfonated ligands that mimic heparan sulfate proteoglycans (HSPG) can exhibit virucidal activity against many viruses that utilize HSPG interactions with host cells for the initial stages of the infection. How the interactions of these nanoparticles with large capsid segments of HSPG-interacting viruses lead to their virucidal activity has been unclear. Here, we describe the interactions between sulfonated nanoparticles and segments of the human papilloma virus type 16 (HPV16) capsids using atomistic molecular dynamics simulations. The simulations demonstrate that nanoparticles primarily bind at interfaces of two HPV16 capsid proteins. Insertions of nanoparticles at these interfaces leads to increased separation in distances and angles between capsid proteins. As the time progresses, the nanoparticle binding can lead to breaking of contacts between two neighboring proteins. The revealed mechanism of nanoparticles targeting the interfaces between pairs of capsid proteins can be utilized for designing new generations of virucidal materials and contribute to the development of new broad-spectrum non-toxic virucidal materials.Abstract Figure