The Role of Electrostatics and Temperature on Morphological Transitions of Hydrogel Nanostructures Self‐Assembled by Peptide Amphiphiles Via Molecular Dynamics Simulations

Abstract

Smart biomaterials that are self-assembled from peptide amphiphiles (PA) are known to undergo morphological transitions in response to specific physiological stimuli. The design of such customizable hydrogels is of significant interest due to their potential applications in tissue engineering, biomedical imaging, and drug delivery. Using a novel coarse-grained peptide/polymer model, which has been validated by comparison of equilibrium conformations from atomistic simulations, large-scale molecular dynamics simulations are performed to examine the spontaneous self-assembly process. Starting from initial random configurations, these simulations result in the formation of nanostructures of various sizes and shapes as a function of the 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.

Sequence-Dependent Structural Stability of Self-Assembled Cylindrical Nanofibers by Peptide Amphiphiles

“…In this study, the value for R, which is interpreted as the degree of hydrophobicity between nonpolar groups and is governed by the particular solvent choice, is kept constant at R = 1/3 based on prior work in our group that has established this reference condition for the formation of prototypical cylindrical nanofibers. 42,44,45 Comparison of our structures 42 showed a high degree of similarity with those observed in experimental structures. 2,12 Moreover, the simulations that were conducted by the Schatz group using atomistic and coarsegrained models 52−54 with explicit solvents produce similar structures as those observed by our simulations.…”

“…42 We performed replica-exchange simulations using both atomistic CHARMM 27 force field 59−61 and ePRIME models to examine the effect of temperature on the folding process of a single PA1 molecule. Equilibrium results showed that both coarse-grained and all-atom models produce similar conformations over a wide range of temperatures.…”

“…50 For the hydrophobic palmitoyl tail, each CH 2 group is represented as a single sphere whose bond distance and fluctuation are extracted from available atomistic parameters. 42 For the system of interest, an implicit solvent model is implemented to reduce the system's size to allow for tractable simulations in order to capture the whole spontaneous self-assembly process. The solvent effect is incorporated into the effective residue−residue potential based on the hydrophobic or hydrophilic character of the corresponding peptide residue or alkyl group.…”

“…In this study, the strength of an electrostatic repulsion between two charges on the glutamic acids, ε ES , is the same as that of the hydrogen bond, ε HB , as it is the optimal condition where cylindrical nanofibers were observed in our previous study. 42 In conjunction with the coarse-grained representation of the system, discontinuous molecular dynamics (DMD) is utilized to enable simulations of large system sizes and extended time scales. As an alternative to standard molecular dynamics, DMD models bonded and nonbonded interactions through discontinuous potentials (e.g., hardsphere and square-well potentials).…”

Multiscale simulation of DNA

“…For example, the WT4 model, which condenses 11 water molecules in four beads, was meant to work in conjunction with the SIRAH force-field [142]. In the same way, the regular and polarized water models by The model developed by Nguyen and coworkers was thought to combine with ePRIME [152], and be delivered as BioModi [149], a unified CG force-field for DNA, proteins and general polymers. The DNA model from Scheraga's group [128] was derived with the same philosophy used to derive the UNRES [153] force-field for proteins, and is expected to be compatible.…”