Stability, metastability and aggregation in Prion proteins: Importance of capturing the rare events

In contrast to the molecular machinery where nature performs fascinatingly well, there are many examples where things may go terribly wrong leading to life-threatening diseases! In this talk we shall try to understand the elusive problem of “prion propagation” and their aggregation into insoluble fibrils that cause a multitude of neurodegenerative disorders. I shall talk about our recent efforts in identifying the mysterious misfolded scrapie (PrP^Sc) form of a prion protein that is considered to infect the healthy cellular prions (PrP^C) by inducing misfolding in them. Using extensive Replica Exchange Molecular Dynamics (REMD) simulations we have been able to identify many low-lying transient misfolded states that might catalyze the aggregation pathway through hydrophobic interactions. We also speculate that the secondary structural elements in a cellular Prion are in fact stabilized by weak tertiary contacts leading to very low barrier towards misfolding.
 
We shall also discuss our futuristic ideas about understanding the hydrophobic effects around a complex molecular surface (e.g. proteins), which seem to play a very important role in various self-assembly, aggregation and binding processes. Our long term goal would be to build a computationally efficient, yet quantitative implicit solvation model that would give us solvation thermodynamics of any arbitrary molecular surface.