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1. Programming co-assembled peptide nanofiber morphology via anionic amino acid type: Insights from molecular dynamics simulations

   https://doi.org/10.1371/journal.pcbi.1011685  

   Dong, Xin Y.; Liu, Renjie; Seroski, Dillon T.; Hudalla, Gregory A.; Hall, Carol K. (December 2023, PLOS Computational Biology)

   Levy, Yaakov Koby (Ed.)

   Co-assembling peptides can be crafted into supramolecular biomaterials for use in biotechnological applications, such as cell culture scaffolds, drug delivery, biosensors, and tissue engineering. Peptide co-assembly refers to the spontaneous organization of two different peptides into a supramolecular architecture. Here we use molecular dynamics simulations to quantify the effect of anionic amino acid type on co-assembly dynamics and nanofiber structure in binary CATCH(+/-) peptide systems. CATCH peptide sequences follow a general pattern: CQCFCFCFCQC, where all C’s are either a positively charged or a negatively charged amino acid. Specifically, we investigate the effect of substituting aspartic acid residues for the glutamic acid residues in the established CATCH(6E-) molecule, while keeping CATCH(6K+) unchanged. Our results show that structures consisting of CATCH(6K+) and CATCH(6D-) form flatter β-sheets, have stronger interactions between charged residues on opposing β-sheet faces, and have slower co-assembly kinetics than structures consisting of CATCH(6K+) and CATCH(6E-). Knowledge of the effect of sidechain type on assembly dynamics and fibrillar structure can help guide the development of advanced biomaterials and grant insight into sequence-to-structure relationships. 

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2. Anatomy of a selectively coassembled β-sheet peptide nanofiber

   https://doi.org/10.1073/pnas.1912810117  

   Shao, Qing; Wong, Kong M.; Seroski, Dillon T.; Wang, Yiming; Liu, Renjie; Paravastu, Anant K.; Hudalla, Gregory A.; Hall, Carol K. (February 2020, Proceedings of the National Academy of Sciences)

   Peptide self-assembly, wherein molecule A associates with other A molecules to form fibrillar β-sheet structures, is common in nature and widely used to fabricate synthetic biomaterials. Selective coassembly of peptide pairs A and B with complementary partial charges is gaining interest due to its potential for expanding the form and function of biomaterials that can be realized. It has been hypothesized that charge-complementary peptides organize into alternating ABAB-type arrangements within assembled β-sheets, but no direct molecular-level evidence exists to support this interpretation. We report a computational and experimental approach to characterize molecular-level organization of the established peptide pair, CATCH. Discontinuous molecular dynamics simulations predict that CATCH(+) and CATCH(−) peptides coassemble but do not self-assemble. Two-layer β-sheet amyloid structures predominate, but off-pathway β-barrel oligomers are also predicted. At low concentration, transmission electron microscopy and dynamic light scattering identified nonfibrillar ∼20-nm oligomers, while at high concentrations elongated fibers predominated. Thioflavin T fluorimetry estimates rapid and near-stoichiometric coassembly of CATCH(+) and CATCH(−) at concentrations ≥100 μM. Natural abundance¹³C NMR and isotope-edited Fourier transform infrared spectroscopy indicate that CATCH(+) and CATCH(−) coassemble into two-component nanofibers instead of self-sorting. However,¹³C–¹³C dipolar recoupling solid-state NMR measurements also identify nonnegligible AA and BB interactions among a majority of AB pairs. Collectively, these results demonstrate that strictly alternating arrangements of β-strands predominate in coassembled CATCH structures, but deviations from perfect alternation occur. Off-pathway β-barrel oligomers are also suggested to occur in coassembled β-strand peptide systems. 

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3. Injectable nanofibrillar hydrogels based on charge-complementary peptide co-assemblies

   https://doi.org/10.1039/D0BM01372B  

   Soto Morales, Bethsymarie; Liu, Renjie; Olguin, Juanpablo; Ziegler, Abigail M.; Herrera, Stephanie M.; Backer-Kelley, Kimberly L.; Kelley, Karen L.; Hudalla, Gregory A. (April 2021, Biomaterials Science)

   null (Ed.)

   Injectable hydrogels are attractive for therapeutic delivery because they can be locally administered through minimally-invasive routes. Charge-complementary peptide nanofibers provide hydrogels that are suitable for encapsulation of biotherapeutics, such as cells and proteins, because they assemble under physiological temperature, pH, and ionic strength. However, relationships between the sequences of charge-complementary peptides and the physical properties of the hydrogels that they form are not well understood. Here we show that hydrogel viscoelasticity, pore size, and pore structure depend on the pairing of charge-complementary “CATCH(+/−)” peptides. Oscillatory rheology demonstrated that co-assemblies of CATCH(4+/4−), CATCH(4+/6−), CATCH(6+/4−), and CATCH(6+/6−) formed viscoelastic gels that can recover after high-shear and high-strain disruption, although the extent of recovery depends on the peptide pairing. Cryogenic scanning electron microscopy demonstrated that hydrogel pore size and pore wall also depend on peptide pairing, and that these properties change to different extents after injection. In contrast, no obvious correlation was observed between nanofiber charge state, measured with ζ-potential, and hydrogel physical properties. CATCH(4+/6−) hydrogels injected into the subcutaneous space elicited weak, transient inflammation whereas CATCH(6+/4−) hydrogels induced stronger inflammation. No antibodies were raised against the CATCH(4+) or CATCH(6−) peptides following multiple challenges in vehicle or when co-administered with an adjuvant. These results demonstrate that CATCH(+/−) peptides form biocompatible injectable hydrogels with viscoelastic properties that can be tuned by varying peptide sequence, establishing their potential as carriers for localized delivery of therapeutic cargoes. 

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4. Molecular complementarity and structural heterogeneity within co-assembled peptide β-sheet nanofibers

   https://doi.org/10.1039/c9nr08725g  

   Wong, Kong M.; Wang, Yiming; Seroski, Dillon T.; Larkin, Grant E.; Mehta, Anil K.; Hudalla, Gregory A.; Hall, Carol K.; Paravastu, Anant K. (February 2020, Nanoscale)

   null (Ed.)

   Self-assembling peptides have garnered an increasing amount of interest as a functional biomaterial for medical and biotechnological applications. Recently, β-sheet peptide designs utilizing complementary pairs of peptides composed of charged amino acids positioned to impart co-assembly behavior have expanded the portfolio of peptide aggregate structures. Structural characterization of these charge-complementary peptide co-assemblies has been limited. Thus, it is not known how the complementary peptides organize on the molecular level. Through a combination of solid-state NMR measurements and discontinuous molecular dynamics simulations, we investigate the molecular organization of King–Webb peptide nanofibers. KW+ and KW− peptides co-assemble into near stoichiometric two-component β-sheet structures as observed by computational simulations and 13 C– 13 C dipolar couplings. A majority of β-strands are aligned with antiparallel nearest neighbors within the β-sheet as previously suggested by Fourier transform infrared spectroscopy measurements. Surprisingly, however, a significant proportion of β-strand neighbors are parallel. While charge-complementary peptides were previously assumed to organize in an ideal (AB) n pattern, dipolar recoupling measurements on isotopically diluted nanofiber samples reveal a non-negligible amount of self-associated (AA and BB) pairs. Furthermore, computational simulations predict these different structures can coexist within the same nanofiber. Our results highlight structural disorder at the molecular level in a charge-complementary peptide system with implications on co-assembling peptide designs. 

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5. Mapping the Morphological Landscape of Oligomeric Di‐block Peptide–Polymer Amphiphiles**

   https://doi.org/10.1002/anie.202115547  

   Allen, Benjamin P.; Wright, Zoe M.; Taylor, Hailey F.; Oweida, Thomas J.; Kader‐Pinky, Sabila; Patteson, Emily F.; Bucci, Kara M.; Cox, Caleb A.; Senthilvel, Abishec Sundar; Yingling, Yaroslava G.; et al (January 2022, Angewandte Chemie International Edition)

   Abstract Peptide–polymer amphiphiles (PPAs) are tunable hybrid materials that achieve complex assembly landscapes by combining the sequence‐dependent properties of peptides with the structural diversity of polymers. Despite their promise as biomimetic materials, determining how polymer and peptide properties simultaneously affect PPA self‐assembly remains challenging. We herein present a systematic study of PPA structure–assembly relationships. PPAs containing oligo(ethyl acrylate) and random‐coil peptides were used to determine the role of oligomer molecular weight, dispersity, peptide length, and charge density on self‐assembly. We observed that PPAs predominantly formed spheres rather than anisotropic particles. Oligomer molecular weight and peptide hydrophilicity dictated morphology, while dispersity and peptide charge affected particle size. These key benchmarks will facilitate the rational design of PPAs that expand the scope of biomimetic functionality within assembled soft materials. 

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