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 (PrPSc) form of a prion protein that is considered to infect the healthy cellular prions (PrPC) 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.