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Synthetic NAC 71-82 Peptides Designed to Produce Fibrils with Different Protofilament Interface Contacts
Umeå University, Faculty of Science and Technology, Department of Physics.
Umeå University, Faculty of Science and Technology, Department of Physics.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-4480-1219
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2021 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 17, article id 9334Article in journal (Refereed) Published
Abstract [en]

Alpha-synucleinopathies are featured by fibrillar inclusions in brain cells. Although α-synuclein fibrils display structural diversity, the origin of this diversity is not fully understood. We used molecular dynamics simulations to design synthetic peptides, based on the NAC 71-82 amino acid fragment of α-synuclein, that govern protofilament contacts and generation of twisted fibrillar polymorphs. Four peptides with structures based on either single or double fragments and capped or non-capped ends were selected for further analysis. We determined the fibrillar yield and the structures from these peptides found in the solution after fibrillisation using protein concentration determination assay and circular dichroism spectroscopy. In addition, we characterised secondary structures formed by individual fibrillar complexes using laser-tweezers Raman spectroscopy. Results suggest less mature fibrils, based on the lower relative β-sheet content for double- than single-fragment peptide fibrils. We confirmed this structural difference by TEM analysis which revealed, in addition to short protofibrils, more elongated, twisted and rod-like fibril structures in non-capped and capped double-fragment peptide systems, respectively. Finally, time-correlated single-photon counting demonstrated a difference in the Thioflavin T fluorescence lifetime profiles upon fibril binding. It could be proposed that this difference originated from morphological differences in the fibril samples. Altogether, these results highlight the potential of using peptide models for the generation of fibrils that share morphological features relevant for disease, e.g., twisted and rod-like polymorphs.

Place, publisher, year, edition, pages
MDPI, 2021. Vol. 22, no 17, article id 9334
Keywords [en]
α-synuclein, NAC 71-82 peptides, fibril polymorphs
National Category
Biochemistry and Molecular Biology Other Physics Topics
Identifiers
URN: urn:nbn:se:umu:diva-186977DOI: 10.3390/ijms22179334ISI: 000694357900001Scopus ID: 2-s2.0-85113788315OAI: oai:DiVA.org:umu-186977DiVA, id: diva2:1588774
Available from: 2021-08-29 Created: 2021-08-29 Last updated: 2023-09-05Bibliographically approved
In thesis
1. KNOW YOUR ENEMY: Characterizing Pathogenic Biomaterials Using Laser Tweezers
Open this publication in new window or tab >>KNOW YOUR ENEMY: Characterizing Pathogenic Biomaterials Using Laser Tweezers
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diseases caused by pathogenic agents such as bacteria and viruses result in devastating costs on personal and societal levels. However, it is not just the emergence of new diseases that is problematic. Antibiotic resistance among bacteria makes uncomplicated infections difficult and lethal. Resilient disease-causing spores spread in hospitals, the food industry, and water supplies requiring effective detection and disinfection methods. Further, we face complex neurological diseases where no effective treatment or diagnostic methods exist. Thus, we must increase our fundamental understanding of these diseases to develop effective diagnostic, detection, disinfection, and treatment methods.

Classically, the methods used for detecting and studying the underlying mechanics of pathogenic agents work on a large scale, measuring the average macroscopic behavior and properties of these pathogens. However, just as with humans, the average behavior is not always representative of individual behavior. Therefore, it is also essential to investigate the characteristics of these pathogens on a single cell or particle level. 

This thesis develops and applies optical techniques to characterize pathogenic biomaterial on a single cell or particle level. At the heart of all these studies is our Optical Tweezers (OT) instrument. OT are a tool that allows us to reach into the microscopic world and interact with it. Finally, by combining OT with other experimental techniques, we can chemically characterize biomaterials and develop assays that mimic different biological settings. Using these tools, we investigate bacterial adhesion, disinfection, and detection of pathogenic spores and proteins.

Hopefully, the insights of these studies can lessen the burden on society caused by diseases by helping others develop effective treatment, diagnostic, detection, and disinfection methods in the future. 

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2022. p. 73
Keywords
Optical Tweezers, Laser Tweezers, Raman Spectroscopy, Bacterial Adhesion, Biophysics, Pili, Bacterial Spores, Endospores, Oocysts, Cryptosporidium, Optics
National Category
Biophysics Atom and Molecular Physics and Optics
Research subject
biology; Physics
Identifiers
urn:nbn:se:umu:diva-192471 (URN)978-91-7855-726-4 (ISBN)978-91-7855-727-1 (ISBN)
Public defence
2022-03-11, NAT.D.410, Naturvetarhuset, Umeå, 09:00 (English)
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Available from: 2022-02-18 Created: 2022-02-14 Last updated: 2022-02-15Bibliographically approved

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Dahlberg, TobiasMalyshev, DmitryÅdén, Jörgen

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