Fibpredictor: a computational method for rapid prediction of amyloid fibril structures

Many peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants were investigated using thioflavin T fluorescence assays, circular dichroism spectroscopy, and structure prediction methods. Our results suggest that those peptide variants with a strong propensity to form an α-helical secondary structure under physiological conditions are more likely to aggregate into amyloid fibrils than peptides in an unstructured or “random coil” conformation. This conclusion is in good agreement with the hypothesis that an α-helical transition state is required for peptide aggregation into amyloid fibrils. Specifically, uperin 3.5 variants in which charged amino acids were replaced by alanine were richer in α-helical content, leading to enhanced aggregation compared to that of wild type uperin 3.5. However, the addition of 2,2,2-trifluoroethanol as a major co-solute or membrane-mimicking phospholipid environments locked uperin 3.5 to the α‑helical conformation preventing amyloid aggregation. Strategies for stabilizing peptides into their α-helical conformation could provide therapeutic approaches for overcoming peptide aggregation-related diseases. The impact of the physiological environment on peptide secondary structure could explain aggregation processes in a cellular environment.

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“…Between these extremes, the peptide rapidly forms β-sheets. Uperin 3.5 wt structures were predicted − and visualized in VMD …”

Section: Resultsmentioning

confidence: 99%

“…The nucleation step might be accelerated by the presence of an α-helical intermediate. Structures predicted − and visualized in VMD . Figure adapted from ref .…”

mentioning

confidence: 99%

The Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide’s Secondary Structure

et al. 2019

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“…2a). Predictive computational modeling with open-access FibPredictor software 42 provided initial evidence that functionalized KLDL Linear and KFDF Linear SAPs would experience a switch in self-assembly orientation from antiparallel to parallel β-sheets. Regardless, such a design would retain the capacity to form fibrillar bilayers (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…FibPredictor was utilized as a commercially available software for generating native-like amyloid fibril structures 42 . This software was chosen for our study due to its unique ability to reliably model all classes of amyloid fibrils starting from sequence-only input.…”

Section: Methodsmentioning

confidence: 99%

Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction

et al. 2019

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Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). However, most hydrogels tested in preclinical studies are not candidates for minimally invasive catheter delivery due to excess material viscosity, rapid gelation times, and/or concerns regarding hemocompatibility and potential for embolism. We describe a platform technology for progelator materials formulated as sterically constrained cyclic peptides which flow freely for low resistance injection, and rapidly assemble into hydrogels when linearized by disease-associated enzymes. Their utility in vivo is demonstrated by their ability to flow through a syringe and gel at the site of MI in rat models. Additionally, synthetic functionalization enables these materials to flow through a cardiac injection catheter without clogging, without compromising hemocompatibility or cytotoxicity. These studies set the stage for the development of structurally dynamic biomaterials for therapeutic hydrogel delivery to the MI.

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“…To model bLg amyloid fibrils that were structurally unknown and likely heterogeneous, two bLg‐amyloid‐forming segments, 117 LACQCL 122 and 41 VYVEELKPTPEG 52 containing ion‐binding cysteines and acidic amino acids, were selected from fragments identified by a mass spectroscopy study of protease‐resistant bLg amyloid fibril cores. [ 92 ] The corresponding fibrillar structures of both sequences were predicted using Fibpredictor [ 93 ] and relaxed in the DMD simulations for 50 ns. For the docking of metal ions with the bLg amyloid, we assigned attractive potentials between the metal ions and cysteine atoms to model coordination bonds.…”

Section: Methodsmentioning

confidence: 99%

Remediation of Metal Oxide Nanotoxicity with a Functional Amyloid

Wang,

Liang,

Andrikopoulos

et al. 2024

Advanced Science

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Understanding the environmental health and safety of nanomaterials (NanoEHS) is essential for the sustained development of nanotechnology. Although extensive research over the past two decades has elucidated the phenomena, mechanisms, and implications of nanomaterials in cellular and organismal models, the active remediation of the adverse biological and environmental effects of nanomaterials remains largely unexplored. Inspired by recent developments in functional amyloids for biomedical and environmental engineering, this work shows their new utility as metallothionein mimics in the strategically important area of NanoEHS. Specifically, metal ions released from CuO and ZnO nanoparticles are sequestered through cysteine coordination and electrostatic interactions with beta‐lactoglobulin (bLg) amyloid, as revealed by inductively coupled plasma mass spectrometry and molecular dynamics simulations. The toxicity of the metal oxide nanoparticles is subsequently mitigated by functional amyloids, as validated by cell viability and apoptosis assays in vitro and murine survival and biomarker assays in vivo. As bLg amyloid fibrils can be readily produced from whey in large quantities at a low cost, the study offers a crucial strategy for remediating the biological and environmental footprints of transition metal oxide nanomaterials.

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Fibpredictor: a computational method for rapid prediction of amyloid fibril structures

Cited by 9 publications

References 42 publications

The Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide’s Secondary Structure

The Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide’s Secondary Structure

Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction

Remediation of Metal Oxide Nanotoxicity with a Functional Amyloid

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