Physics-Based Simulation of HSV Surface Glycoproteins to Inform Vaccine Design

Herpes Simplex Virus (HSV) infects a significant portion of the global adult population. Though this virus may remain dormant after acute infection, it has been known to resurface and have serious potential side effects. HSV is an enveloped, double-stranded DNA virus that enters host cells via endocytosis. HSV cell entry depends on four essential surface glycoproteins, with glycoprotein D (gD) mediating the crucial receptor-binding step. While the dynamics of this process have been studied with respect to nectin and HVEM as essential receptors, there are no studies involving the in silico dynamics of glycoprotein D binding to its initial co-receptor, 3-O-sulfated heparan sulfate (HS). Due to the ability of HSV to establish latency, it can evade the immune response, resulting in the lack of any effective licensed vaccine. Studying the molecular dynamics of the gD binding interaction with heparan sulfate, and how it may influence following protein-protein interactions, will potentially inform a structurally based vaccine design.

To address this, we modeled the initial state of gD using AlphaFold3, finalizing glycan locations for structural accuracy. Molecular dynamics simulations of the gD monomer in solution, performed with GROMACS, resulted in a stable structure, providing a promising basis for further study. Additional optimizations, such as hydrogen mass repartitioning, were explored to enhance simulation capabilities. Next, we will simulate the gD dimer in complex with heparan sulfate in an intracellular environment to assess any conformational changes induced by secondary receptor binding. The results of this simulation will be essential in uncovering the individual mechanisms involved in the viral cell entry process, to ultimately inform structure-based HSV vaccines.