Molecular, Local, and Network-Level Basis for the Enhanced Stiffness of Hydrogel Networks Formed from Coassembled Racemic Peptides: Predictions from Pauling and Corey

Nagy-Smith, Katelyn; Beltramo, Peter J.; Moore, Eric W.; Tycko, Robert; Furst, Eric M.; Schneider, Joel P.

doi:10.1021/acscentsci.7b00115

Cited by 126 publications

(144 citation statements)

References 83 publications

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“…Integration of 1‐ 13 C‐labeled amino acids was conducted in each sequence pattern of 2‐Nal‐substituted peptides as the incorporation of the heavier 13 C carbonyl group results in the shift of the amide I stretch due to the lower vibrational frequency. This shift of the amide I stretch is magnified when 13 C labeled carbonyls are in close proximity within the cross‐strand registry of a β‐sheet fibril, moving the signal to an even lower wavenumber . A substitution of each 2‐Nal sequence with a single 1‐ 13 C label at Lys 6 resulted in the amide I stretch shifting from ∼1616 cm −1 on the unlabeled peptides (Figure ) to ∼1600 cm −1 on the singly labeled peptides (Figure ).…”

Section: Resultsmentioning

confidence: 97%

“…Solvent ionic strength, pH, and temperature strongly influence β‐sheet peptide self‐assembly and the emergent properties of the self‐assembled materials . In addition, peptide sequence order, repeat unit length (n), charge, and chirality also have a strong impact on self‐assembly . We and others, have shown that hydrophobicity and β‐sheet propensity are critical parameters for promoting the self‐assembly of amphipathic β‐sheet peptides .…”

Section: Introductionmentioning

confidence: 98%

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Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

2018

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Amphipathic peptides with alternating polar and nonpolar amino acid sequences efficiently selfassemble into functional b-sheet fibrils as long as the nonpolar residues have sufficient hydrophobicity. For example, the Ac-(FKFE) 2 -NH 2 peptide rapidly self-assembles into b-sheet bilayer nanoribbons, while Ac-(AKAE) 2 -NH 2 fails to self-assemble under similar conditions due to the significantly reduced hydrophobicity and b-sheet propensity of Ala relative to Phe. Herein, we systematically explore the effect of substituting only two of the four Ala residues at various positions in the Ac-(AKAE) 2 -NH 2 peptide with amino acids of increasing hydrophobicity, b-sheet potential, and surface area (including Phe, 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), cyclohexylalanine (Cha), and pentafluorophenylalanine (F 5 -Phe)) on the self-assembly propensity of the resulting sequences. It was found that double Phe variants, regardless of the position of substitution, failed to self-assemble under the conditions used in this study. In contrast, all double 1-Nal and 2-Nal variants readily self-assembled, albeit at differing rates depending on the substitution patterns. To determine whether this was due to hydrophobicity or side chain surface area, we also prepared double Cha and F 5 -Phe variant peptides (both side chain groups are more hydrophobic than Phe). Each of these variants also underwent effective self-assembly, with the aromatic F 5 -Phe peptides doing so with greater efficiency. These findings provide insight into the role of amino acid hydrophobicity and sequence pattern on self-assembly proclivity of amphipathic peptides and on how targeted substitutions of nonpolar residues in these sequences can be exploited to tune the characteristics of the resulting self-assembled materials.hydrophobicity, peptide, self-assembly | I N TR ODU C TI ONThe development of biomaterials derived from self-assembled peptides is of great current interest due to biomedical applications including controlled release drug delivery, vaccine development, tissue engineering, and wound healing. Amphipathic peptides that consist of alternating hydrophobic and hydrophilic amino acids are a privileged class of peptide that readily self-assembles into b-sheet bilayer nanoribbons that share the basic characteristics of cross-b amyloid assemblies (Figure 1). [23][24][25][26][27][28][29][30] These bilayer nanoribbons effectively sequester all hydrophobic functionality to the bilayer interior, leaving hydrophilic groups exposed to solvent on the exterior face. [24,[31][32][33][34] As a result, these nanoribbons maintain high solubility in aqueous solvents, making them ideal materials for biological applications. Because of the high utility of this class of amphipathic peptide, they have been widely adopted as models to study the fundamental physicochemical basis of peptide self-assembly processes in order to facilitate the rational design of next-generation materials derived from self-assembled b-sheet peptides.[ [35][36][37][38][39]...

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Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

2018

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“…Whereas strong experimental evidence has been provided by the Schneider and the Nillson laboratories that racemic mixtures of short peptides likely assemble to form rippled cross‐β configurations, there is, to the best of our knowledge, not a single high‐resolution rippled cross‐β structure available yet. The rac ‐Aβ40 system may offer a unique opportunity to obtain the first such structure in the future.…”

Section: Discussionmentioning

confidence: 99%

“…The rac ‐Aβ40 system may offer a unique opportunity to obtain the first such structure in the future. There is a broad significance in the heterochiral molecular recognition phenomena that underlie the formation of rippled cross‐β structures, ranging from materials, as well as biomedical applications, to phenomena related to origins of life and chirality of biospheres …”

Section: Discussionmentioning

confidence: 99%

New insights into differential aggregation of enantiomerically pure and racemic Aβ40 systems

et al. 2019

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Racemic mixtures frequently display properties that are different from those associated with their enantiopure counterparts, and are often characterized by higher propensity to form aggregates. Our previous research established that mixing of the enantiomers of Alzheimer amyloid β (Aβ) 42 peptides is an effective strategy to induce an oligomer‐to‐fibril conversion, which puts Aβ42 into a substantially less toxic state. Here, new insights into this chiral inactivation effect are presented. In addition to the commonly used Thioflavin T fibril formation assays, the use of the less aggregation‐prone Aβ40 system allowed us to monitor peptide aggregation by NMR. Whereas enantiopure peptide was well soluble under the chosen experimental conditions and showed no sign of precipitation, addition of one equivalent of the mirror‐image peptide triggered an instant and rapid aggregation, observable through the attenuation of the NMR signal. The racemic Aβ40 fibrils were found by transmission electron microscopy to be distinct in morphology, exhibiting a ~2‐fold narrowing as compared with their enantiopure counterparts.

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“…98 When the relative ratios of two gelators are mixed, we have also found that there can be a non-linear effect on the absolute moduli. 103 Interestingly, Nagy-Smith et al 106 have recently shown that mixing two gelators that are simply the enantiomeric isomers of each other results in the formation of a co-assembled system. The rheological data show that the co-assembled gel is much stiffer than those formed by either of the enantiomerically pure gelators.…”

Section: Multicomponent Systemsmentioning

confidence: 99%

Low-Molecular-Weight Gels: The State of the Art

Draper

Adams

2017

Chem

536

469

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Low-molecular-weight gels are currently a hugely important class of materials that are attracting significant interest. These gels are formed when small molecules self-assemble into one-dimensional structures that entangle and cross-link to form a network that is capable of immobilizing the solvent. Here, we critically discuss the current state of the art and highlight two key areas where we believe there is significant untapped potential. The first is the observation that the properties of the gels are highly process dependent, which means that it is possible to access materials with very different properties from a single gelator. Second, using multiple gelators offers the opportunity to prepare materials with a high degree of information content and with a wider range of properties. We aim to spark thought and discussion on these aspects. INTRODUCTIONLow-molecular-weight gels (LMWGs), or supramolecular gels, are a fascinating and useful class of material. The gels arise from the self-assembly of small molecules into long, anisotropic structures, most commonly fibers. [1][2][3][4][5] At a sufficiently high concentration, these fibers entangle or otherwise form cross-links, leading to the network that is able to immobilize the solvent through surface tension and capillary forces. 1,2 These gels differ from permanently covalently cross-linked polymer gels because the cross-linking can be reversed by the input of energy, for example, by heating. 6 LMWGs have been around for many years but are receiving considerable current interest. 4 They are also used in industrial products, 7 although this seems rarely discussed in the academic literature.In addition to the industrial applications, many recent advances and uses are being described. [8][9][10][11][12] The specific self-assembly leading to gel formation can be exploited. For example, the fiber formation is a result of molecular stacking, meaning that the self-assembly leads to aggregates that can be suitable for optoelectronic applications. 13,14 The ready reversibility of gelation can be exploited, for example, to release cells from gels on demand in a manner that does not lead to cell death. 15 Ready gel formation by a simple trigger can also be used to allow easy and efficient gel loading. [16][17][18] Unsurprisingly, therefore, there is significant interest in these materials ( Figure 1). This is a fascinating area and in many ways holds attention because of the difficulties in probing and understanding the gels. The gels arise from assembly across many length scales, and understanding all of these is difficult. At the molecular level, the molecules must interact in a manner that leads to the formation of suitable aggregates that can eventually entangle. Thus, one-dimensional growth must be favored. From this perspective, it is very frustrating that it is often extremely difficult to predict whether a molecule will form a gel or not; indeed, gelation has been described as an empirical science. 4 Structurally similar small molecules can exhibitThe Bigger Pict...

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Molecular, Local, and Network-Level Basis for the Enhanced Stiffness of Hydrogel Networks Formed from Coassembled Racemic Peptides: Predictions from Pauling and Corey

Cited by 126 publications

References 83 publications

Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

Balancing hydrophobicity and sequence pattern to influence self‐assembly of amphipathic peptides

New insights into differential aggregation of enantiomerically pure and racemic Aβ40 systems

Low-Molecular-Weight Gels: The State of the Art

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