(144a) Invited Talk: Multi-Scale Modeling of the pH-Controlled Self-Assembly By Peptide Amphiphiles

Self-assembling nanomaterials that can change shape or structure in response to environmental stimuli hold a great promise to revolutionize medicine and biotechnology. However, current discovery is slow and often serendipitous; therefore, there is a great need in detailed, predictive modeling. Here we report a multi-scale modeling study based on two state-of-the-art techniques to elucidate pH-dependent morphological transition between spherical micelles and cylindrical nanofibers that are self-assembled from peptide amphiphiles (PA), palmitoyl-I-A₃E₄-NH₂. The coarse-grained molecular dynamics simulations revealed that self-assembly of spherical micelles is driven by hydrophobic interactions between alkyl tails when the electrostatic repulsion is strong. Merging of these micelles into nanofibers is driven by β-sheet formation between the peptide segments when the electrostatic repulsion is weak. The all-atom constant pH molecular dynamics simulations revealed a cooperative transition between random coil (as exhibited in micelles) and β-sheet (as exhibited in nanofibers) in the pH range 6–7, in agreement with experiment. Interestingly, although the bulk pK_a is more than one unit below the transition pH, consistent with experiment, the highest pK_a’s coincide with the transition pH, suggesting that the latter may be tuned by modulating the pK_a’s of a few solvent-buried Glu sidechains. Taken together, the present study illustrates a multiscale modeling strategy that may aid in the design and discovery of pH-responsive nanomaterials.