(269h) A Simulation-Based Thermodynamic Model to Pre-Screen Peptide Amphiphile Micelle Vaccines

Vaccines have been one of mankind’s greatest public health achievement with their rapid development having become ever more important due to the COVID-19 pandemic. While traditional strategies employing whole-killed or live-attenuated vaccines have been successful, the emergence of new subunit and nucleic-acid-based vaccines require new engineered devices to be broadly efficacious. An exciting alternative vaccine delivery technology is the peptide amphiphile micelle (PAM) system. This modular platform technology offers the potential to reduce the obstacles of de novo vaccine development, as incorporated immunogenic peptides and molecular adjuvants can be readily changed. Specifically, the shape and size of these PAMs is known to be directly linked to their ability to elicit adaptive immune responses. While promising, the incorporation of new peptides and/or adjuvants can alter micellar architecture, so a method to predict micelle structure a priori would be incredibly helpful to expediting vaccine research. With this in mind, we are developing a molecular thermodynamic model employing molecular dynamics simulations to screen bioactive peptide amphiphile (PA) candidates for their self-assembled micelle morphology and size. Specifically, the free energy of micellization is decomposed into the sum of different physical contributions, including that of the hydrophobic effect, and a new method for estimating the role of headgroup interactions is posed. To test our model, a method for defining particle shape has been developed and used to generate size distributions to compare to those derived from experimental small-angle x-ray scattering (SAXS) and TEM. Once fully developed, a computation-based approach for screening PA vaccine candidates holds tremendous potential for achieving truly “warp speed” vaccine development.