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 this project series we embark on an effort to characterize which force field and water models most accurately recapitulate tau experimental results.
We believe these findings will be broadly applicable to all researchers studying intrinsically disordered proteins, and aspire to keep performing these benchmarking simulations as new force field and waters are released.
We also expect these simulations to yield useful information about the tau conformational ensemble. 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 8000 MiB to run 182[51-56,58,61,62].
and 12000 MiB to run 182[57,60] p18251 - amber99sb-disp with tip4pd water p18255- amber14sb with tip3p water p18256- amber03 with tip3p water p18257- amber19sb with opc water p18258- amber19sb with opc3 water p18260- amber99sb-star-ILDN with tip4p water p18261- amber19sb with opc3 pol water p18262 - charmm36m with tip3p water p18263 - amber99sb-star-ILDN with tip4pd water p18264 - amber99sb-star-ILDN with tip3p water.