Dokument: Thermodynamic and conformational analysis of monomeric Aβ isoforms binding with Aβ(1-42) fibril - insights into the secondary nucleation of amyloidosis

Titel:	Thermodynamic and conformational analysis of monomeric Aβ isoforms binding with Aβ(1-42) fibril - insights into the secondary nucleation of amyloidosis
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=59926
URN (NBN):	urn:nbn:de:hbz:061-20220620-140910-3
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	M.Sc. Nath, Soumav [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 14,39 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 15.06.2022 / geändert 15.06.2022
Beitragende:	Jun.-Prof. Büll, Alexander [Gutachter] Dr. Barz, Bogdan [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Understanding the molecular basis for the plausible occurrence of cross-seeding secondary nucleation in AD pathology is important since the human brain contains various Aβ isoforms like pE-Aβ(3-42) peptide besides full-length Aβ(1-40/42) peptides. This thesis aims towards understanding the thermodynamic insights into the secondary nucleation of monomeric Aβ isoforms, pE-Aβ(3-42) & Aβ(1-42) peptide on the Aβ(1-42) fibril surface and investigating the process at the atomic scale through the analysis of monomeric conformations of these Aβ isoforms both in the presence/absence of fibril surface, leading a pathway towards under- standing the mechanistic insights and developing potential molecular candidates for a ther- apeutic approach in AD pathology. Conformational analysis of IDPs using MD simulations depends on the choice of initial parameters. Chapter 2 establishes CHARMM36mW force- field/HREMD method as the good choice of initial parameters for conformational analysis of Aβ(1-42) peptide, which not only shows greater resemblance with the observed experimen- tal parameters but also for the first time showed that Aβ(1-42) monomer can significantly adopt the S-shaped fibril-like conformation which impels towards higher aggregation propen- sity of fibril elongation for Aβ(1-42) peptide in-vivo. Chapter 3 establishes the significant differences in the monomeric structure of pE-Aβ(3-42) peptide compared with that of Aβ(1- 42) monomer obtained through computational study using the same set of parameters from Chapter 2. The pE-Aβ(3-42) monomer has more exposed hydrophobic residues, two unique salt bridges and a free D23 residue for inter-peptide interaction besides a higher β-sheet and helix propensity per residue compared to that of Aβ(1-42) monomer. This structural dissimilarity seems to be accountable for the observed higher aggregation propensity and tox- icity of the pE-Aβ(3-42) monomer in bulk solution compared to that of Aβ(1-42) monomer. In Chapter 4, combined results from surface-based bio-sensing experiments show that the binding mode of pE-Aβ(3-42) to the Aβ(1-42) fibril surface is pH-dependent and it has a higher affinity compared to that of Aβ(1-42) monomer. Computational investigation reveals the possible binding sites for both Aβ isoforms, along with the comparison of free energy of binding and subsequent secondary structural changes between the two isoforms upon binding with the fibril surface. The outcomes rationalize the previously observed behaviour of inhi- bition of cross-secondary nucleation of pE-Aβ(3-42) monomers by Aβ(1-42) fibrils, through exclusive tighter binding of the monomer to the hydrophobic side of the fibril surface and increase in β-sheet propensity per residue compared to that of Aβ(1-42) monomer. Together the whole thesis signifies the investigation of the mixed peptides system to under- stand the insights into the in-vivo mechanism of AD pathology and the potential of combined experimental-cum-computational methodology, using a wise choice of initial parameters for the later one which paves the pathway for the investigation through complementing each other in the manner of understanding the observable from the bulk solution to atomic-scale.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie » Physikalische Biologie
Dokument erstellt am:	20.06.2022
Dateien geändert am:	20.06.2022
Promotionsantrag am:	12.04.2022
Datum der Promotion:	12.05.2022