@article{0da8066141ec44b8a5cf19ec8205779c,
title = "Peptide Sequence Determines Structural Sensitivity to Supramolecular Polymerization Pathways and Bioactivity",
abstract = "Pathways in supramolecular polymerization traverse different regions of the system's energy landscape, affecting not only their architectures and internal structure but also their functions. We report here on the effects of pathway selection on polymerization for two isomeric peptide amphiphile monomers with amino acid sequences AAEE and AEAE. We subjected the monomers to five different pathways that varied in the order they were exposed to electrostatic screening by electrolytes and thermal annealing. We found that introducing electrostatic screening of E residues before annealing led to crystalline packing of AAEE monomers. Electrostatic screening decreased intermolecular repulsion among AAEE monomers thus promoting internal order within the supramolecular polymers, while subsequent annealing brought them closer to thermodynamic equilibrium with enhanced β-sheet secondary structure. In contrast, supramolecular polymerization of AEAE monomers was less pathway dependent, which we attribute to side-chain dimerization. Regardless of the pathway, the internal structure of AEAE nanostructures had limited internal order and moderate β-sheet structure. These supramolecular polymers generated hydrogels with lower porosity and greater bulk mechanical strength than those formed by the more cohesive AAEE polymers. The combination of dynamic, less ordered internal structure and bulk strength of AEAE networks promoted strong cell-material interactions in adherent epithelial-like cells, evidenced by increased cytoskeletal remodeling and cell spreading. The highly ordered AAEE nanostructures formed porous hydrogels with inferior bulk mechanical properties and weaker cell-material interactions. We conclude that pathway sensitivity in supramolecular synthesis, and therefore structure and function, is highly dependent on the nature of dominant interactions driving polymerization.",
author = "Yuan, {Shelby C.} and Lewis, {Jacob A.} and Hiroaki Sai and Weigand, {Steven J.} and Palmer, {Liam C.} and Stupp, {Samuel I.}",
note = "Funding Information: This research was supported by a gift from Mike and Mary Sue Shannon to the Simpson Querrey Institute at Northwestern University for research on musculoskeletal regeneration. Additional support was provided by the Center for Regenerative Nanomedicine at the Simpson Querrey Institute. The authors are grateful to the Peptide Synthesis Core and the Analytical BioNanotechnology Equipment Core of the Simpson Querrey Institute at Northwestern University. These facilities have support from the Soft and Hybrid Nanotechnology Experimental (ShyNE) Resource (NSF ECCS-2025633). The Simpson Querrey Institute, Northwestern University Office for Research, U.S. Army Research Office, and the U.S. Army Medical Research and Materiel Command have also provided funding to develop this facility. Imaging was performed at the Center for Advanced Microscopy (CAM) at Northwestern University, which is supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Solution X-ray experiments were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, E.I. DuPont de Nemours & Co., and The Dow Chemical Company. Use of APS, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. CD was performed at the Northwestern University{\textquoteright}s Keck Biophysics Facility. This work made use of the IMSERC Physical Characterization facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), and Northwestern University. This work also made use of the EPIC facility of the Northwestern NUANCE center, which has received support from the ShyNE Resource (NSF ECCS – 1542205); the MRSEC program (NSF DMR – 1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); the Keck Foundation; and the State of Illinois, through the IIN. Publisher Copyright: {\textcopyright} 2022 American Chemical Society. All rights reserved.",
year = "2022",
month = sep,
day = "14",
doi = "10.1021/jacs.2c05759",
language = "English (US)",
volume = "144",
pages = "16512--16523",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "36",
}