Molecular dynamic simulation studies of three novel Gerstmann - Straussler - Scheinker and Creutzfeldt - Jacob Prion mutations
The transformation of normal prion protein into pathogenic variant in transmissible spongiform encephalopathy (TSE) is expedited by mutations. Three novel mutations V176G, E196A and I215V are associated with Creutzfeldt-Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS). These mut...
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| Format: | Thesis |
| Language: | English |
| Published: |
2016
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| Subjects: | |
| Online Access: | http://eprints.utm.my/id/eprint/77851/1/AshrafFadhilJomahPFBME2016.pdf |
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| Summary: | The transformation of normal prion protein into pathogenic variant in transmissible spongiform encephalopathy (TSE) is expedited by mutations. Three novel mutations V176G, E196A and I215V are associated with Creutzfeldt-Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS). These mutations are novel but have yet to be characterized. The V176G mutation is exceptional as it showed GSS symptoms but resides in CJD prone segment of the prion structure. Using molecular dynamics simulations; comparative studies were performed between wild type and mutated structures, normal and elevated temperature and neutral and acidic pH to identify the dynamics in structural properties such as salt bridge, solvent accessibility, hydrogen bonds and hydrophobicity. Results indicated that overall effect of the three mutants is destabilization of the native structure, increased hydrophobicity and electrostatic potential change and the gain of new hydrogen bonds but are only restricted to localized effects on the protein such as increased fluctuation of the H1 region, gain of new salt bridge in H3 and abolished salt bridges between H1 and H3 which may be part of the oligomerisation pathways similar to GSS. The two CJD mutations, the E196A and I215V that possess a proximity effect on neighbouring regions of the mutated area. Simulations at elevated temperatures showed that the mutation caused the loss of hydrogen bonds between H3 and H2 with perturbations in the hydrophobic core that induces changes in the overall prion protein structure. In the V176G MD simulations, the mutation biggest effect is on the H1 of the protein where extreme conditions (elevated temperature and low pH) caused early denaturation compared to other segments of the prion protein. These mutations also caused accelerated perturbation in the H1-S2 region and extended the existing S1 and S2. Simulations at different low pH regimes revealed that V176G, E196A and I215V mutated structures denatured earlier in pH 2.5 compared to pH 4.5 with increased fluctuations in H1, S2-H2 loop and H2-H3 loop. In conclusion, the apparent loss of salt bridges and hydrogen bond gains are the main reason for the conformational changes that occur in mutated structure. |
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