A computer-simulation-based molecular-thermodynamic model for shape-based screening of peptide amphiphile micelles in vaccines

Peptide amphiphiles (PAs) and their self-assembled aggregates, peptide amphiphile micelles (PAMs), have garnered considerable attention as a platform for biomedical applications due to their unique combination of biocompatibility, modular functionality, and tailorable size and shape. Since PAMs form a wide range of structures (e.g., fibers, vesicles, globular aggregates, nanosheets) and their morphology strongly correlates with their bioactivity, understanding equilibrium micelle shape is of considerable academic and practical interest, particularly when it comes to the engineering of the structure of a PA to achieve a desired function. Reliable prediction of self-assembled shape and computational throughput capacity put opposing constraints on an already complex task as inter-aminoacid interactions preclude conventional concepts, such as the molecular packing parameter from the surfactant community, from providing an adequate description of micellization and detailed all-atom simulations are necessary to model the aggregation behavior. To accommodate these criteria, computer-simulation-inspired molecular thermodynamic models exploit atomic resolution information derived from molecular dynamics simulations for estimating their parameters. Within these models, the shape-dependence contribution to the free energy of micellization is accounted for by simulation of micelles deemed spherical, cylindrical, or planar by qualitative inspection. Furthermore, such classification is limited to spherical/globular, periodic cylindrical, or lamellar shapes, without the capacity to characterize the real morphologies lying at the transition between idealized shapes often observed in PAMs. We present a unique, quantitative means for classifying the shape of molecular-dynamics-simulated PAMs that is both consistent with existing metrics and extendable to estimating shape-dependent free energy contributions. Then, we incorporate this shape-dependent classification scheme and free-energy contribution into a computersimulation- inspired molecular thermodynamic model for the prediction of micellization of Palm2K-NA-(KE)4 PAMs. We show that predictions from this model agree with existing theoretical studies and can quantitatively account for the free energy changes due to interactions between the backbones of peptides such as those associated with [beta]-sheet formation. The dependence of the shape of PAMs on factors such as the hydrophobic effect and interactions between peptide head groups is assessed.

Name thesis:degree_name

Ph. D.

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemical engineering (MU)

Grantor dc:publisher

University of Missouri--Columbia

Year dc:date.issued

2024

Author dc:creator

• Kruse, Luke Everett

Advisors dc:contributor.advisor

• Hammond, Karl D.
• Ulery, Bret D.

Language dc:language.iso

eng, English

DOI

https://doi.org/10.32469/10355/105033

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/105033