Solid-State NMR Evidence for β-Hairpin Structure within MAX8 Designer Peptide Nanofibers

Leonard, Sarah R.; Cormier, Ashley R.; Pang, Xiaodong; Zimmerman, Maxwell I.; Zhou, Huan‐Xiang; Paravastu, Anant K.

doi:10.1016/j.bpj.2013.05.047

Cited by 24 publications

(23 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Amyloid fibrils formed in vitro are generally polymorphic unless special fibril growth protocols are used, such as repeated seeding (8) or long periods of incubation with agitation to promote convergence to a single structure with lowest free energy (35). Prior solid-state NMR studies of the gel-forming peptides RADA16-I and MAX8 suggested polymorphism or incomplete molecular structural order within the hydrogels (14,20).…”

Section: Discussionmentioning

confidence: 99%

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Nagy-Smith

Moore

Schneider

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

127

View full text Add to dashboard Cite

Most, if not all, peptide-and protein-based hydrogels formed by self-assembly can be characterized as kinetically trapped 3D networks of fibrils. The propensity of disease-associated amyloidforming peptides and proteins to assemble into polymorphic fibrils suggests that cross-β fibrils comprising hydrogels may also be polymorphic. We use solid-state NMR to determine the molecular and supramolecular structure of MAX1, a de novo designed gelforming peptide, in its fibrillar state. We find that MAX1 adopts a β-hairpin conformation and self-assembles with high fidelity into a double-layered cross-β structure. Hairpins assemble with an in-register Syn orientation within each β-sheet layer and with an Anti orientation between layers. Surprisingly, although the MAX1 fibril network is kinetically trapped, solid-state NMR data show that fibrils within this network are monomorphic and most likely represent the thermodynamic ground state. Intermolecular interactions not available in alternative structural arrangements apparently dictate this monomorphic behavior.M AX1 is a 20-residue peptide designed de novo to fold into an amphiphilic β-hairpin that self-assembles to form a fibrillar network within a self-supporting hydrogel (1). The MAX1 gel exhibits shear thin-recovery rheological behavior (2), is cytocompatible toward mammalian cells, yet is inherently antimicrobial (3) and thus has applications in tissue engineering and drug delivery. In addition to exploring the utility of the gel, we seek to understand the mechanism of gelation, the macroscale morphology of its fibrillar network, and the underlying molecular structure of its fibrils.MAX1 contains two segments of alternating lysine and valine residues, connected by a four-residue turn-forming segment. When initially dissolved in water, electrostatic repulsions among protonated lysine sidechains lead to an ensemble of monomeric random coil conformations (1). Peptide folding and self-assembly, leading to gelation (Fig. 1), can be triggered by attenuating electrostatic repulsions, by adjusting the solution pH and/or ionic strength. Increasing the solution temperature also drives hydrophobic collapse of valine sidechains, further favoring MAX1 assembly. According to circular dichroism (1), cryo-transmission electron microscopy (TEM) (4), small-angle neutron scattering (5), and dynamic light scattering coupled with rheological measurements (4), soon after the triggering event, peptides assemble into branched clusters of β-sheet-rich, semiflexible nanofibrils throughout the solution. Individual clusters contain dangling fibril ends that grow and interpenetrate neighboring clusters as the network evolves. Multiple particle tracking microrheology shows that the time at which the fibril network percolates the entire sample volume, defining the gel point, is less than 1 min at 1% (wt/vol) peptide (6). In this mechanism of gelation, the growing fibrils become kinetically trapped in the evolving network as they percolate the sample volume. Fibrils do not precipitate, but rather ...

show abstract

Section: Discussionmentioning

confidence: 99%

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Nagy-Smith

Moore

Schneider

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

123

127

View full text Add to dashboard Cite

show abstract

“…As with their naturally occurring counterparts, structural studies of these designer amyloids benefit from valuable insights enabled by ssNMR [23, 114–118]. In most cases, these amyloid- or cross-β-based materials are based on short amyloidogenic peptides that may be modified with acyl chains or by cross-linking [23, 115, 116].…”

Section: Designer Amyloidsmentioning

confidence: 99%

“…This includes the parallel β-sheet solenoids as illustrated in Fig. 2, as well as antiparallel architectures with and without β-hairpins[20, 42, 100, 118]. …”

Section: Recurring Themesmentioning

confidence: 99%

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Wel

2017

Solid State Nuclear Magnetic Resonance

View full text Add to dashboard Cite

The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation. A central focus is on disease-related amyloid fibrils and oligomers involved in neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s disease. SSNMR-enabled structural and dynamics-based findings are surveyed, along with a number of resulting emerging themes that appear common to different amyloidogenic proteins, such as their compact alternating short-β-strand/β-arc amyloid core architecture. Concepts, methods, future prospects and challenges are discussed.

show abstract

“…Nuclei with a spin quantum number of I = ½ such as 1 H, 13 C, 19 F, 29 Si, 15 N, and 31 P yield highresolution NMR spectra and are therefore particularly informative in the study of polymer systems. These nuclei display spectra with unique peaks for each magnetically inequivalent nuclei in the chemical structure, essentially enabling the study of individual atomic positions within the chemical structure of a polymer [3].…”

Section: Nmr Spectroscopy Of Solid Polymersmentioning

confidence: 99%

“…MAX8 is an amphiphilic peptide composed of 20 amino acids, having the amino acid sequence VKVKVKVKVDPPTKVEVKVKVNH2, where K and E are hydrophilic residues and V hydrophobic residues [15]. The self-assembled peptide contains a β-strand hairpin structure aligned into antiparallel β-sheets.…”

Section: Protein Systemsmentioning

confidence: 99%

Developments in Solid-State NMR Spectroscopy of Polymer Systems

Martínez‐Richa¹,

Silvestri²

2017

Spectroscopic Analyses - Developments and Applications

View full text Add to dashboard Cite

Solid-state nuclear magnetic resonance (NMR) has long emerged as a valuable technique for characterizing the molecular structure, conformation, and dynamics of polymer chains in various polymer systems. The principles of the solid-state 13 C NMR cross-polarization experiment are described along with corresponding relaxation measurements. The ensuing recent applications of these techniques to different polymer systems are reviewed, with selected examples that have appeared in the recent literature. All of these applications of solid-state NMR to polymers have one feature in common: the interpretation of spectroscopic observations as related to the structural features and physical properties of the polymer.

show abstract

Solid-State NMR Evidence for β-Hairpin Structure within MAX8 Designer Peptide Nanofibers

Cited by 24 publications

References 61 publications

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Molecular structure of monomorphic peptide fibrils within a kinetically trapped hydrogel network

Insights into protein misfolding and aggregation enabled by solid-state NMR spectroscopy

Developments in Solid-State NMR Spectroscopy of Polymer Systems

Contact Info

Product

Resources

About