Official Project Description
Alzheimer's disease is a significant cause of death and memory loss and there are no effective treatments to halt or reverse disease progression.
One of the late hallmarks and primary biomarkers of Alzheimer's disease is the presence of neurofibrillary tangles, intracellular aggregates of the tau protein.
When behaving properly, tau interacts with microtubules- a critical portion of the cytoskeleton of cells- to help regulate their growth and stability.
However, tau misbehavior and aggregation is also closely linked to Alzheimer's disease among many other neurodegenerative diseases. Studying tau experimentally has been difficult as it is an Intrinsically Disordered Protein (IDP).
As such, traditional structural biology approaches are unable to capture the conformational states of tau in atomistic detail.
Recently, our collaborators have utilized single molecule FRET experiments to experimentally characterize tau by measuring the pairwise distance between different regions.
While simulations of tau could provide atomistic detail of the tau conformational ensemble, historically simulations of IDPs have been challenging as force fields (the parameters which govern the underlying physics of a simulation) and their accompanying models of waters have favored well-folded proteins.
In project p18251-18264, we looked at a portion of tau (the proline rich region) and sought to compare our results to experimentally observed features of tau (see here - https://foldingathome.org/2026/02/19/force-field-comparisons/).
Now, we aim to simulate the entire protein in the best force field/water model. N.B.
because tau is an intrinsically disordered protein, it can fully unfold and refold quite rapidly.
To ensure the protein remains in water the entire simulation, we have included a large number of waters in the system.
As a result these simulations are a good deal more RAM intensive than prior FAH simulations.
Accordingly, we have implemented a minimum system memory requirement of 64Gb to run this project.
Similarly network requirements are significant.
We have attempted to set points accordingly for the increased system usage.