Supramolecular Structure and Stability of the GNNQQNY β-Sheet Bilayer Filament: A Computational Study

Author(s):  
Jiyong Park ◽  
Byungnam Kahng ◽  
Wonmuk Hwang

Self-assembly of β-sheet forming peptides into filaments has drawn great interests in biomedical applications [1,2]; Hydrogels formed by filaments self-assembled from de novo designed peptides possess potential applications for cell culture scaffolds [3]. On the other hand, peptides derived from amyloidogenic proteins in neurodegenerative diseases such as Alzheimer’s and Parkinson’s also form similar β-sheet filaments in vitro. They share little sequence homology, yet filaments formed by these self-assembling peptides commonly have the cross-β structure, the key signature of the amyloid fibril. Detailed structural information of the self-assembled β-sheet filaments has been limited partly due to the difficulty in preparing ordered filament samples, and it has been only recently that solid-state nuclear magnetic resonance and x-ray techniques have revealed their molecular structure at the atomic level [4,5]. Although molecular structures of amyloid fibrils are becoming available, physical principles governing their self-assembly and the properties of the filaments are not well-understood, for which computational as well as theoretical approaches are desirable [6].

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Moein Dehbashi ◽  
Zohreh Hojati ◽  
Majid Motovali-bashi ◽  
Mazdak Ganjalikhani-Hakemi ◽  
Akihiro Shimosaka ◽  
...  

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.


2004 ◽  
Vol 377 (3) ◽  
pp. 709-716 ◽  
Author(s):  
Emma T. A. S. JAIKARAN ◽  
Melanie R. NILSSON ◽  
Anne CLARK

Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.


Author(s):  
Maarten C Hardenberg ◽  
Tessa Sinnige ◽  
Sam Casford ◽  
Samuel Dada ◽  
Chetan Poudel ◽  
...  

Abstract Misfolded α-synuclein is a major component of Lewy bodies, which are a hallmark of Parkinson’s disease. A large body of evidence shows that α-synuclein can aggregate into amyloid fibrils, but the relationship between α-synuclein self-assembly and Lewy body formation remains unclear. Here we show, both in vitro and in a Caenorhabditis elegans model of Parkinson’s disease, that α-synuclein undergoes liquid‒liquid phase separation by forming a liquid droplet state, which converts into an amyloid-rich hydrogel with Lewy-body-like properties. This maturation process towards the amyloid state is delayed in the presence of model synaptic vesicles in vitro. Taken together, these results suggest that the formation of Lewy bodies may be linked to the arrested maturation of α-synuclein condensates in the presence of lipids and other cellular components.


2002 ◽  
Vol 30 (4) ◽  
pp. 521-525 ◽  
Author(s):  
O. S. Makin ◽  
L. C. Serpell

The pathogenesis of the group of diseases known collectively as the amyloidoses is characterized by the deposition of insoluble amyloid fibrils. These are straight, unbranching structures about 70–120 å (1 å = 0.1 nm) in diameter and of indeterminate length formed by the self-assembly of a diverse group of normally soluble proteins. Knowledge of the structure of these fibrils is necessary for the understanding of their abnormal assembly and deposition, possibly leading to the rational design of therapeutic agents for their prevention or disaggregation. Structural elucidation is impeded by fibril insolubility and inability to crystallize, thus preventing the use of X-ray crystallography and solution NMR. CD, Fourier-transform infrared spectroscopy and light scattering have been used in the study of the mechanism of fibril formation. This review concentrates on the structural information about the final, mature fibril and in particular the complementary techniques of cryo-electron microscopy, solid-state NMR and X-ray fibre diffraction.


2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Peng Zhang ◽  
Manola Moretti ◽  
Marco Allione ◽  
Yuansi Tian ◽  
Javier Ordonez-Loza ◽  
...  

AbstractMethods to produce protein amyloid fibrils, in vitro, and in situ structure characterization, are of primary importance in biology, medicine, and pharmacology. We first demonstrated the droplet on a super-hydrophobic substrate as the reactor to produce protein amyloid fibrils with real-time monitoring of the growth process by using combined light-sheet microscopy and thermal imaging. The molecular structures were characterized by Raman spectroscopy, X-ray diffraction and X-ray scattering. We demonstrated that the convective flow induced by the temperature gradient of the sample is the main driving force in the growth of well-ordered protein fibrils. Particular attention was devoted to PHF6 peptide and full-length Tau441 protein to form amyloid fibrils. By a combined experimental with the molecular dynamics simulations, the conformational polymorphism of these amyloid fibrils were characterized. The study provided a feasible procedure to optimize the amyloid fibrils formation and characterizations of other types of proteins in future studies.


RSC Advances ◽  
2015 ◽  
Vol 5 (4) ◽  
pp. 2794-2805 ◽  
Author(s):  
Lin Zhou ◽  
Xuefeng Ge ◽  
Jiahong Zhou ◽  
Shaohua Wei ◽  
Jian Shen

Self-assembled photosensitizer nanostructures preparation by controlling the charge property of drug and ion strength of environment to improve photodynamic activity.


2009 ◽  
Vol 1209 ◽  
Author(s):  
Eric L. Bruner

AbstractAculon, Inc. specializes in inventing and commercializing unique molecular-scale surface and interfacial coatings leveraging nanotechnology discoveries made at Princeton University. These coatings can be classified into three functional areas; non-stick, pro-stick/adhesion, and anti-corrosion. The company has formulated coating solutions and processes for numerous markets including optical, display, electronics, consumer products and industrial coatings. These specialized coatings outperform all known alternatives in characteristics such as adhesion, stain resistance, and scratch resistance. Fueling the company’s commercialization efforts are its proprietary Self-Assembled Monolayer of Phosphonates (SAMP) technology. The commercialization of SAMP treatments can be used for a variety of applications including imparting hydrophobicity, adhesion, or corrosion inhibition to numerous substrates. For surface treatments to be effective, they must be mechanically and chemically stable under conditions experienced in the intended area of use. Aculon’s proprietary Self-Assembled Monolayer of Phosphonates methodology can impart any of these properties as desired to metals, metal oxides and even some polymer surfaces by drawing on its library of structurally tailored phosphonic acids. The secret to the commercialization is covalent bonding, which creates a uniquely strong attachment between the SAMP and the substrate. Because the SAMP is one approximately 1.5 nm thick, it completely covers the material to which it is applied, and assures total surface coverage regardless of the type or texture of that material. The composition of the SAMP determines the properties that it imparts to its substrate. In 1998, Professor Jeffery Schwartz of Princeton University discovered that well-ordered monolayers of phosphonates could be formed by self-assembly on a wide variety of oxide and oxide-terminated surfaces. At that time Professor Schwartz and his team also discovered that a simple dip process enabled SAMP formation on substrates of complex structures and geometries, as well as traditionally “unreactive” surfaces. The research showed that SAMP adhesion to oxides was mechanically strong and resisted removal by hydrolysis and oxidation. It showed further that by using the dip method, SAMPs of a variety of molecular structures, including aliphatic, aromatic, and heteroaromatic, could be prepared. Commercialization of SAMPs proves that such surface-bound phosphonates can dictate control of the surface properties of myriad substrates and that they can be implemented using well-known industrial techniques and conditions. These processes can be scaled to meet the needs of large or small facilities, and can be applied to surfaces of nearly any size or shape without special needs. Based on the needs of the producer, surface modification can be completed during the time of manufacturing or can be performed as a post-production step.


2019 ◽  
Vol 116 (36) ◽  
pp. 17963-17969 ◽  
Author(s):  
Katsuya Araki ◽  
Naoto Yagi ◽  
Koki Aoyama ◽  
Chi-Jing Choong ◽  
Hideki Hayakawa ◽  
...  

Many neurodegenerative diseases are characterized by the accumulation of abnormal protein aggregates in the brain. In Parkinson’s disease (PD), α-synuclein (α-syn) forms such aggregates called Lewy bodies (LBs). Recently, it has been reported that aggregates of α-syn with a cross-β structure are capable of propagating within the brain in a prionlike manner. However, the presence of cross-β sheet-rich aggregates in LBs has not been experimentally demonstrated so far. Here, we examined LBs in thin sections of autopsy brains of patients with PD using microbeam X-ray diffraction (XRD) and found that some of them gave a diffraction pattern typical of a cross-β structure. This result confirms that LBs in the brain of PD patients contain amyloid fibrils with a cross-β structure and supports the validity of in vitro propagation experiments using artificially formed amyloid fibrils of α-syn. Notably, our finding supports the concept that PD is a type of amyloidosis, a disease featuring the accumulation of amyloid fibrils of α-syn.


2020 ◽  
Vol 48 (9) ◽  
pp. 5135-5146 ◽  
Author(s):  
Christopher Maffeo ◽  
Aleksei Aksimentiev

Abstract Although the field of structural DNA nanotechnology has been advancing with an astonishing pace, de novo design of complex 3D nanostructures and functional devices remains a laborious and time-consuming process. One reason for that is the need for multiple cycles of experimental characterization to elucidate the effect of design choices on the actual shape and function of the self-assembled objects. Here, we demonstrate a multi-resolution simulation framework, mrdna, that, in 30 min or less, can produce an atomistic-resolution structure of a self-assembled DNA nanosystem. We demonstrate fidelity of our mrdna framework through direct comparison of the simulation results with the results of cryo-electron microscopy (cryo-EM) reconstruction of multiple 3D DNA origami objects. Furthermore, we show that our approach can characterize an ensemble of conformations adopted by dynamic DNA nanostructures, the equilibrium structure and dynamics of DNA objects constructed using off-lattice self-assembly principles, i.e. wireframe DNA objects, and to study the properties of DNA objects under a variety of environmental conditions, such as applied electric field. Implemented as an open source Python package, our framework can be extended by the community and integrated with DNA design and molecular graphics tools.


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