Thermal, Chemical and Mechanical Stability of HPV L1 VLP Vaccines: A Multiscale All-Atom Simulation Study

Abstract

Recently Virus-like-Particles (VLPs) have been used as vaccines against viral diseases. It is the structural similarity of VLPs, and the surface proteins (epitopes) that evokes a neutralizing antibody response. We present a novel computational approach which may ultimately be applied in cell-free synthesis of VLP-based vaccines that are stable over wide range of external environmental conditions (e.g. temperature). Moreover, we aim to construct VLPs that can be stored and dressed later with different epitopes depending on the target virus, addressing wide range of viral diseases in a fast, cost-effective manner in unfolding pandemic scenarios.Here we present computational studies on VLPs constructed from a major capsid protein (L1) of human papilloma virus (HPV). The thermal stability and structural dynamics of these VLPs was studied using our novel multiscale all-atom approach. We probed mechanical stability via a bottom-up approach starting from major L1 protein going eventually up to the complete VLPs. External force was applied to each of these systems to probe their response to external tension. We have found the unfolding pathways of L1 proteins. Forces were applied to probe the strength of interface interactions between (1) L1 proteins and (2) pentameric assemblies of these protomers that form the subunits of a complete VLP. Finally we performed fully atomistic force-probe MD simulations of the complete VLPs in explicit solvent. Forces were applied at different positions on the viral surface. A detailed picture of the spatial distribution of elastic constants and yielding forces was obtained.All these results together helped us to understand thermal, chemical and mechanical stability of HPV VLPs. These will be used to make appropriate predictions of mutations in the structures to achieve our long term goal of constructing more stable VLPs.