Self-Assembly of Stimuli-Responsive Hydrogel Nanostructures by Peptide Amphiphiles via Molecular Dynamics Simulations

Abstract

Peptide amphiphiles (PA), which have been known to self-assemble into nanostructures such as cylindrical nanofibers and spherical micelles in hydrogel, are of significant interest due to their potential applications in tissue engineering, biomedical imaging, and drug delivery. A representative PA molecule is comprised of a hydrophobic alkyl tail, a short peptide sequence for intermolecular hydrogen bonding, a group of charged amino acids for enhanced solubility, and a region for bioactive signals to be transduced via cells or proteins. Smart biomaterials that are self-assembled from such PA molecules are known to undergo morphological transitions in response to specific physiological stimuli. Using a novel coarse-grained peptide/polymer model, which has been validated by comparison of equilibrium conformations from atomistic simulations, we have performed large-scale molecular dynamics simulations to examine the whole spontaneous self-assembly process (1). Starting from random configurations, these simulations result in the formation of nanostructures of various sizes and shapes as a function of electrostatics and temperature. At optimal conditions, the self-assembly mechanism for the formation of cylindrical nanofibers is deciphered involving a series of steps: (1) PA molecules quickly undergo micellization whose driving force is the hydrophobic interactions between alkyl tails; (2) neighboring peptide residues within a micelle engage in a slow ordering process that leads to the formation of β-sheets exposing the hydrophobic core; (3) spherical micelles merge together through an end-to-end mechanism to form cylindrical nanofibers that exhibit high structural fidelity to the proposed structure based on experimental data. As the temperature and electrostatics vary, PA molecules undergo alternative kinetic mechanisms, resulting in the formation of a wide spectrum of nanostructures. A phase diagram in the electrostatics-temperature plane is constructed delineating regions of morphological transitions in response to external stimuli. (1) doi: 10.1002/adhm.201200400.