Molecular dynamic simulation studies of Q212H, V203G and N173K mutations in prion diseases
The Prion protein (PrP) roots from a collection of diseases identified as transmissible spongiform encephalopathies (TSEs), which are caused by conversion of PrP from its normal cellular form (PrPC) to a misfolded, oligomeric isoform (PrPSc). Prion diseases are considered fatal and until now no know...
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| Format: | Thesis |
| Language: | English |
| Published: |
2014
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| Subjects: | |
| Online Access: | http://eprints.utm.my/id/eprint/48011/25/SaraAmidianFBME2014.pdf |
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| Summary: | The Prion protein (PrP) roots from a collection of diseases identified as transmissible spongiform encephalopathies (TSEs), which are caused by conversion of PrP from its normal cellular form (PrPC) to a misfolded, oligomeric isoform (PrPSc). Prion diseases are considered fatal and until now no known treatment has been reported. Prion diseases in humans are grouped based on whether they are sporadic, inherited, or acquired. In the case of inherited prion disease, which is also known as familial prion disease, abnormal prion proteins are produced through a genetic mutation. So far, about 40 point mutations have been discovered. The globular domain (aa125 to 228) of PrP plays a critical role in its folding and stability and many of pathogenic mutations are located on this part. V203G, Q212H and N173K are three PRNP mutations, which were reported recently, but it remained questionable whether the mutations were causal of the disease. In this research, we preformed Molecular Dynamic Simulation and structural analysis on the three previously mentioned unknown-disease-related mutations (V203G, Q212H and N173K) and prion disease related mutations V203I and Q212P as positive control for V203G and Q212H respectively and neutral polymorphism N171S as a negative control for N173K. We investigated to see how similar the unknown-disease-related mutations act compared to their controls, to verify whether the mutations were causal of the disease. 50 ns of molecular dynamic simulations were performed for all mutations and wild type, using GROMACS 4.6.3 software and GROMS96 force field. Changes in RMSD, RMSF, salt bridges, secondary structure and Solvent accessible surface area were explored by analyzing the trajectories. The results revealed similar dynamic behavior between Q212H, V203G, N173K and other prion pathogenic mutations; all three under study mutations showed a decrease in the protein’s overall stability, an increase in HB and HC region flexibility, a major loss in salt bridges in the HA and HB region, changes in the electrostatic surface of PrP and made the protein more exposed to solvent, which are all common dynamic behaviors among pathogenic mutations |
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