A computational approach was developed for the design of HPV virus-like particles (VLPs) that could evoke a neutralizing antibody response. The approach is based on the SimNanoWorld(TM) software built on advanced statistical physics methods for simulating nanosystem behavior. These methods allow the calibration-free simulation of a whole VLP with all-atom resolution over biologically relevant time periods. This approach yields the changing position of each atom within the VLP so that the interatomic forces and strength of interactions between VLPs and antibodies or other features in the microenvironment can be determined. SimNanoWorld(TM) predicts the stability of VLPs of given peptide sequence, allowing the discovery of modifications that may be stable in various temperature conditions, for example.

By predicting the geometry of epitope presentation under various conditions or of interaction with antibodies, quantitative measures of likely vaccine efficacy are obtained. These measures are used in Quantitative Structure Activity Relationship or Artificial Intelligence approaches to vaccine design. By designing VLPs with epitopes of multiple HPV types, cross-protection could potentially be enhanced. The approach was validated using data from simulations of HPV 31 L1 protein VLPs (see Figure 1). Modifications to include L2 proteins can similarly be simulated to predict stability and response to changes in conditions, as well as to computationally evaluate their interactions with antibodies. We believe this computer-aided vaccine design approach could yield a paradigm shift in vaccine development.

Figure1: Atom-resolved HPV 31 VLP structure investigated for stability and self-assembly by SimNanoWorld(TM) as part of a computer-aided vaccine design workflow. The HPV VLP is comprised of 72 pentameric L1 assemblies. Left Panel: complete L1 VLP. Right B: L1 pentamers surrounded by either five others (shown in yellow) or six others (shown in red). There are 12 pentagonal arrangements and 60 hexagonal ones in a complete VLP.