Project Summary/Abstract Viral infections kill millions of people every year. Current antiviral drugs have many limitations, including non- specificity for viral proteins that can result in host toxicity, drug resistance that develops through rapid virus mutations, and the lack of a broad-spectrum applicability. There is a critical need to develop broad-spectrum and non-toxic antiviral therapeutics. One promising approach is to use virucidal materials as therapeutics, which can cause irreversible viral deactivation. Recently, it was observed that nanoparticles with long and flexible ligands mimicking a virus cell receptor heparan sulfate proteoglycans (HSPG), a common cell receptor for many viruses, allow for effective viral association and eventually lead to irreversible deformation of many HSPG-targeting viruses. These nanoparticles were shown to be active ex vivo in human cervicovaginal histocultures infected by herpes simplex virus 2 and in vivo in mice infected with respiratory syncytial virus. In this proposal, we will use atomistic molecular dynamics simulations to examine these novel virucidal materials jointly with experimental collaborators, with these aims: 1) Determine the molecular origin of virucidal activity of HSPG-mimicking ligated metal core nanoparticles, resulting in irreversible deformations of viruses upon binding; 2) In collaboration with experimentalists, determine the virucidal mechanisms of newly developed HSPG-mimicking ligated nanoconstructs with molecular cores and aid in their optimal design. In particular, we will explore how ligand charge, length, and chemistry affect interactions of the above materials with viral capsid segments (focusing on HPV-16, whose capsid structure has been determined). Completion of the proposed aims will reveal essential virucidal mechanisms of new materials, and will lead to determining the key principles for the future design of related second generation virucidal substances.