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1. A hybrid approach for coarse-graining helical peptoids: Solvation, secondary structure, and assembly

   https://doi.org/10.1063/5.0138510  

   Banerjee, Akash; Dutt, Meenakshi (March 2023, The Journal of Chemical Physics)

   Protein mimics such as peptoids form self-assembled nanostructures whose shape and function are governed by the side chain chemistry and secondary structure. Experiments have shown that a peptoid sequence with a helical secondary structure assembles into microspheres that are stable under various conditions. The conformation and organization of the peptoids within the assemblies remains unknown and is elucidated in this study via a hybrid, bottom-up coarse-graining approach. The resultant coarse-grained (CG) model preserves the chemical and structural details that are critical for capturing the secondary structure of the peptoid. The CG model accurately captures the overall conformation and solvation of the peptoids in an aqueous solution. Furthermore, the model resolves the assembly of multiple peptoids into a hemispherical aggregate that is in qualitative agreement with the corresponding results from experiments. The mildly hydrophilic peptoid residues are placed along the curved interface of the aggregate. The composition of the residues on the exterior of the aggregate is determined by two conformations adopted by the peptoid chains. Hence, the CG model simultaneously captures sequence-specific features and the assembly of a large number of peptoids. This multiscale, multiresolution coarse-graining approach could help in predicting the organization and packing of other tunable oligomeric sequences of relevance to biomedicine and electronics. 

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2. 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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3. Designing phenylalanine-based hybrid biological materials: controlling morphology via molecular composition

   https://doi.org/10.1039/c8ob00130h  

   Mushnoori, Srinivas; Schmidt, Kassandra; Nanda, Vikas; Dutt, Meenakshi (January 2018, Organic & Biomolecular Chemistry)

   Harnessing the self-assembly of peptide sequences has demonstrated great promise in the domain of creating high precision shape-tunable biomaterials. The unique properties of peptides allow for a building block approach to material design. In this study, self-assembly of mixed systems encompassing two peptide sequences with identical hydrophobic regions and distinct polar segments is investigated. The two peptide sequences are diphenylalanine and phenylalanine-asparagine-phenylalanine. The study examines the impact of molecular composition (namely, the total peptide concentration and the relative tripeptide concentration) on the morphology of the self-assembled hybrid biological material. We report a rich polymorphism in the assemblies of these peptides and explain the relationship between the peptide sequence, concentration and the morphology of the supramolecular assembly. 

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4. Factors Affecting Secondary and Supramolecular Structures of Self‐Assembling Peptide Nanocarriers

   https://doi.org/10.1002/mabi.202100347  

   Pitz, Megan E.; Nukovic, Alexandra M.; Elpers, Margaret A.; Alexander‐Bryant, Angela A. (November 2021, Macromolecular Bioscience)

   Abstract Self‐assembling peptides are a popular vector for therapeutic cargo delivery due to their versatility, tunability, and biocompatibility. Accurately predicting secondary and supramolecular structures of self‐assembling peptides is essential for de novo peptide design. However, computational modeling of such assemblies is not yet able to accurately predict structure formation for many peptide sequences. This review identifies patterns in literature between secondary and supramolecular structures, primary sequences, and applications to provide a guide for informed peptide design. An overview of peptide structures, their applications as nanocarriers, and analytical methods for characterizing secondary and supramolecular structure is examined. A top‐down approach is then used to identify trends between peptide sequence and assembly structure from the current literature, including an analysis of the drivers at work, such as local and nonlocal sequence effects and solution conditions. 

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5. Pathways of amyloid-beta absorption and aggregation in a membranous environment

   https://doi.org/10.1039/C9CP00040B  

   Sahoo, Abhilash; Xu, Hongcheng; Matysiak, Silvina (April 2019, Physical Chemistry Chemical Physics)

   Aggregation of misfolded oligomeric amyloid-beta (Aβ) peptides on lipid membranes has been identified as a primary event in Alzheimer's pathogenesis. However, the structural and dynamical features of this membrane assisted Aβ aggregation have not been well characterized. The microscopic characterization of dynamic molecular-level interactions in peptide aggregation pathways has been challenging both computationally and experimentally. In this work, we explore differential patterns of membrane-induced Aβ 16–22 (K–L–V–F–F–A–E) aggregation from the microscopic perspective of molecular interactions. Physics-based coarse-grained molecular dynamics (CG-MD) simulations were employed to investigate the effect of lipid headgroup charge – zwitterionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phosphocholine: POPC) and anionic (1-palmitoyl-2-oleoyl- sn-glycero -3-phospho- l -serine: POPS) – on Aβ 16–22 peptide aggregation. Our analyses present an extensive overview of multiple pathways for peptide absorption and biomechanical forces governing peptide folding and aggregation. In agreement with experimental observations, anionic POPS molecules promote extended configurations in Aβ peptides that contribute towards faster emergence of ordered β-sheet-rich peptide assemblies compared to POPC, suggesting faster fibrillation. In addition, lower cumulative rates of peptide aggregation in POPS due to higher peptide–lipid interactions and slower lipid diffusion result in multiple distinct ordered peptide aggregates that can serve as nucleation seeds for subsequent Aβ aggregation. This study provides an in-silico assessment of experimentally observed aggregation patterns, presents new morphological insights and highlights the importance of lipid headgroup chemistry in modulating the peptide absorption and aggregation process. 

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