A molecular dynamics study of the prion protein

dc.contributor.advisor Balta, Bülent
dc.contributor.author Tavşanlı, Ayşenaz
dc.contributor.authorID 521152101
dc.contributor.department Molecular Biology-Genetics and Biotechnology
dc.date.accessioned 2024-01-25T08:20:20Z
dc.date.available 2024-01-25T08:20:20Z
dc.date.issued 2023-05-12
dc.description Thesis(Ph.D.) -- Istanbul Technical University, Graduate School, 2023
dc.description.abstract Transmissible spongiform encephalopathies are caused by the conversion of the cellular prion protein PrPC into a misfolded form, PrPSc. In sheep populations there is a polymorphism at positions 136 (alanine/valine), 154 (arginine/histidine) and 171 (arginine/glutamine). While the A136-R154-R171 (ARR) variant confers highest resistance to scrapie, the V136-R154-Q171 (VRQ) variant leads to highest scrapie susceptibility. The A136-R154-Q171 (ARQ) variant with intermediate resistance is considered as wild type. To identify important conformational rearrangements at the initial steps of misfolding, microseconds long restrained and unrestrained molecular dynamics simulations have been prefomed at neutral pH, at 310 K and 330 K on naturally existing prion variants. Also, unfolding potentials of all three helicas of prion protein structure were also conducted at differentiated temperatures with the help of replica exchange molecular dynamic simulations. Moreover, at differentiated pH conditions unfolding potential of helix 1 and interaction of helix 1 with some other sequences were also conducted. Susceptibility of the disease might be related to hyrophobic side chain of the valine at position 136 which seemed to ease the unfolding process. While arginine at position 171 worked as a clamp to keep helix 2 and helix 3 of the cellular prion protein structure together. That might be the reason why VRQ is the most susceptable one where ARR is the most resistance. On the other hand, unfolding of helix 1 played the most critical role since it was the most stable helical structure in all conducted simulations. Inter- and/or intramolecular salt bridges of helix 1 were important to keep helix 1 stable in both helical structure and/or unfolded structure. Energy calculation showed that not high energy was needen to unwind helix 1. This helical structure of hydrophilic H1 might be broken by another hydrophilic sequence of the same prion protein, and its unwinding might be the key point to catalyze the complete unfolding of the protein
dc.description.degree Ph. D.
dc.identifier.uri http://hdl.handle.net/11527/24450
dc.language.iso en_US
dc.publisher Graduate School
dc.sdg.type Goal 9: Industry, Innovation and Infrastructure
dc.subject proteins
dc.subject proteinler
dc.subject prions
dc.subject prionlar
dc.title A molecular dynamics study of the prion protein
dc.title.alternative Prıon proteinin moleküler dinamik simülasyonları ile araştırılması
dc.type Doctoral Thesis
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