Molecular Dynamics Simulations of Glycosylated Prion Protein

• Author / Creator

  Sekar, Rohith Vedhthaanth

• While PrP is almost always found in the glycosylated state, there has been very little study attempting to explore the effects of the size of glycans, the composition of glycans, and the site of glycosylation on the stability of PrP. These effects can potentially play an important role in the misfolding of PrP (conversion of PrPC to PrPSc), the cause of neurodegenerative prion diseases, either directly or indirectly. Glycosylation patterns found in the brain are different in different regions of the brain, and the disease vulnerability also varies across different parts of the brain, suggesting that glycans could play a role in the infectivity. Glycosylation patterns are also a key characteristic of infectious prion strains. Previous studies on other glycoprotein systems suggest that glycans impact the stability, structure, aggregation rates, and other properties of the protein they are attached to. These properties play a crucial role in the context of PrP misfolding. The difficulty associated with carrying out site specific chemical glycosylation, the large number of glycans that can attach to PrP, and multiple sites of glycosylation in PrP (N181 and N197) make it hard to carry out experiments to systematically explore the effects of the size of glycans, the composition of glycans and the site of glycosylation on PrP.
  To explore these effects systematically, we performed molecular dynamics simulations of mono glycosylated and diglycosylated PrP using glycans that differ in size and composition. The behaviour of glycosylated PrP across all the simulations were compared. Our computational simulations provide insights into possible glycan-PrP interactions. Our results show that the glycan-PrP interaction is affected minimally by the bulkiness of the glycans, but the presence of sialic acid groups strengthens the interaction significantly. We also show that a glycan attached at a site of glycosylation, can take on multiple conformations and can affect the stability of different parts of the protein depending on the conformation it adopts. More importantly, we report events where glycans induce unfolding within the PrP and we identify the segments of PrP that are vulnerable to such unfolding effects.

• Subjects / Keywords

  • Prion Protein
  • Glycosylation
  • Molecular dynamics

• Graduation date

  Spring 2021

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-k4sf-1v47

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.