(165n) A Molecular Dynamics-Based, Molecular Thermodynamic Model to Pre-Screen Tomorrow’s Vaccines

Due to the COVID-19 pandemic, fundamental research to accelerate the vaccine development process has become of the utmost importance. Peptide amphiphiles (PAs), consisting of a lipid region covalently tethered to a biologically active peptide (BAP), provide an exciting platform technology for vaccine development as this allows for new vaccine development to be reduced to that of swapping out the BAP for the next emerging purpose. As a consequence of their amphiphilic nature, PAs self-assemble into peptide amphiphile micelles (PAMs) when placed in aqueous environments, the shape and size of these PAMs is known to be directly linked to their ability to elicit adaptive immune responses. We are developing a simulation-based, molecular thermodynamic model to screen therapeutic PA candidates by their self-assembled micelle morphology and size. To test the predictions of our model, SAXS profiles produced from molecular dynamics (MD) simulations of PAMs are compared to experimental results. Contributions to and parameters involved in estimating the change in free energy of micellization, including those from hydrophobic effects, are calculated from our simulations and are found to be comparable to those obtained in prior studies. We also investigate the ability of MD simulations to reproduce experimental secondary structure distributions and predict NMR T1 and T2 relaxation times. The final result is a thermodynamic model for screening PA vaccine candidates. This technique holds tremendous potential for achieving truly “warp speed” vaccine development.