Mehanizem stabilizacije humanega transportnega proteina transtiretina z rožmarinsko kislino

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Title:	Mehanizem stabilizacije humanega transportnega proteina transtiretina z rožmarinsko kislino
Authors:	ID Kočevar, Meta (Author) ID Bren, Urban (Mentor) More about this mentor... ID Lešnik, Samo (Comentor)
Files:	MAG_Kocevar_Meta_2024.pdf (4,82 MB) MD5: D4589AA5A568787C9AD12E3F9DB3CB20
Language:	Slovenian
Work type:	Master's thesis/paper
Typology:	2.09 - Master's Thesis
Organization:	FKKT - Faculty of Chemistry and Chemical Engineering
Abstract:	Dedna transtiretinska amiloidoza je avtosomno dominantna bolezen. Nastane kot posledica mutacije v proteinu transtiretinu. Mutacije povzročajo strukturne spremembe proteina, ki jim sledi disociacija v monomere in kasneje agregacija monomerov ter tvorba amiloidnih vlakenc. Vlakenca se nalagajo v tkivih kot so živčevje, srce in ledvice. Nestabilno strukturo proteina, ki jo povzročajo mutacije, je možno stabilizirati z vezavo majhnih molekul na protein. Ena izmed takšnih molekul je rožmarinska kislina. V magistrskem delu smo z uporabo računalniških simulacij molekulske dinamike ugotavljali, kako mutacija V30M vpliva na stabilnost strukture proteina transtiretina. Na protein smo vezali tudi rožmarinsko kislino in opazovali, ali se z vezavo stabilnost proteina spremeni. Pri tem smo uporabili dva različna načina parametrizacije polja sil za rožmarinsko kislino. Za pripravo 6 simulacij molekulske dinamike smo uporabili program CHARMM-GUI, za samo izvedbo simulacij pa program NAMD. Rezultate smo vizualno pregledali in analizirali s programoma Chimera in Cytoscape. Analiza trajektorij molekulskih dinamik je obsegala izračun srednjega kvadrata odstopanja, analizo vodikovih vezi in analizo vseh nekovalentnih kontaktov. Rezultati, ki smo jih pri tem dobili, kažejo, da mutacija V30M povzroči manj stabilno strukturo transtiretina. Avtomatsko parametrizirana rožmarinska kislina na stabilnost kompleksa protein-ligand za nemutirani protein ni imela velikega vpliva, medtem ko je ročno parametrizirana rožmarinska kislina zmanjšala število kontaktov med nemutiranim proteinom in ligandom. V primeru vezave ročno parametrizirane rožmarinske kisline pa smo zaznali veliko število kontaktov med proteinom in ligandom. Ob vezavi rožmarinske kisline na nemutirani protein smo zaznali manjšo stabilnost proteina. Vezava rožmarinske kisline na mutirani protein pa izboljša stabilnost proteina.
Keywords:	transtiretin, transtiretinska amiloidoza, rožmarinska kislina, simulacije molekulske dinamike, polje sil, stabilnost proteina
Place of publishing:	Maribor
Year of publishing:	2024
PID:	20.500.12556/DKUM-90305
Publication date in DKUM:	10.10.2024
Views:	0
Downloads:	25
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Categories:	KTFMB - FKKT
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Licences

License:	CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International

Link:	http://creativecommons.org/licenses/by-nc-nd/4.0/
Description:	The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.
Licensing start date:	28.08.2024

Secondary language

Language:	English
Title:	Stabilisation mechanism of the human transthyretin transporter protein by rosmarinic acid
Abstract:	Hereditary transthyretin amyloidosis is an autosomal dominant disease. The disease is caused by a mutation in the transthyretin protein. Mutations cause structural changes in the protein, followed by dissociation into monomers and subsequent aggregation of the monomers to form amyloid fibrils. Fibrils are deposited in organs such as the nervous system, heart and kidneys. The unstable protein structure caused by mutations can be stabilised by binding small molecules to the protein. One such molecule is rosmarinic acid. In this thesis, we used computational molecular dynamics simulations to determine how the V30M mutation affects the stability of the structure of the transthyretin protein. We also bound rosmarinic acid to the protein and observed whether the binding changes the stability of the protein. Two different ways of the force field parameterisation for rosmarinic acid were used. We applied CHARMM-GUI to prepare the 6 molecular dynamics simulations and NAMD to run them. The results were visually examined and analysed using Chimera and Cytoscape. The analysis of the molecular dynamics trajectories included the calculation of the Root Mean Square Deviation, the analysis of hydrogen bonds and the analysis of all non-covalent contacts. The results obtained show that the V30M mutation results in a less stable transthyretin structure. The stability of the protein-ligand complex for the non-mutated protein was not significantly affected by the automatically parameterised rosmarinic acid, whereas the manually parameterised rosmarinic acid reduced the number of contacts between the non-mutated protein and the ligand. However, in the case of binding manually parameterised rosmarinic acid, a high number of contacts between the protein and the ligand was detected. Binding of rosmarinic acid to the mutated protein improves the stability of the protein. However, when rosmarinic acid was bound to the non-mutated protein, we detected lack of stability of the protein itself.
Keywords:	transthyretin, transthyretin amyloidosis, rosmarinic acid, molecular dynamics simulations, force field, protein stability

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