RESEARCH: ALZHEIMERS
FOLDING PROJECT #18261 PROFILE

Alzheimer's disease causes memory loss and there's no cure. A protein called tau goes bad in the brain, forming harmful clumps. This project uses computer simulations to study how tau works, finding the best way to model it. This will help scientists understand Alzheimer's and other diseases better.

Note: This TLDR is a simplication and may not be 100% accurate.

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 accompyning 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].

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 tip4pd water p18261- amber19sb with opc3 pol water p18262 - charmm36m with tip3p water.

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Alzheimer's disease

A progressive neurodegenerative disorder affecting memory and cognitive function.

Alzheimer's disease is a serious brain disorder that causes memory loss, thinking problems, and behavioral changes. It is the most common cause of dementia.

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neurofibrillary tangles

Twisted fibers of tau protein found in brain cells of people with Alzheimer's disease.

Neurofibrillary tangles are abnormal accumulations of tau protein inside nerve cells. They are a hallmark of Alzheimer's disease and contribute to the damage of brain cells.

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tau protein

A microtubule-associated protein involved in stabilizing and regulating the structure of neurons.

Tau is a protein that plays an important role in maintaining the structure of nerve cells. In Alzheimer's disease, tau becomes abnormal and forms tangles, which damage brain cells.

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microtubules

Long, hollow protein fibers that form part of the cytoskeleton and are involved in cell shape, transport, and division.

Microtubules are tiny tubes made of proteins that act as a scaffolding within cells. They help maintain cell shape, transport materials, and play a role in cell division.

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cytoskeleton

A network of protein fibers that provides support and structure to cells.

The cytoskeleton is a complex network of protein filaments that gives cells their shape, helps them move, and plays a role in transporting materials within the cell.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a well-defined three-dimensional structure.

Intrinsically disordered proteins (IDPs) are proteins that do not have a fixed shape. They can adopt different conformations depending on their environment and interactions with other molecules.

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force field

A set of mathematical equations that describe the interactions between atoms in a molecular simulation.

Force fields are used in computer simulations to model the behavior of molecules. They provide a way to calculate the forces acting between atoms and predict how molecules will move and interact.

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FRET

Förster Resonance Energy Transfer.

FRET is a technique used to measure the distance between two molecules labeled with fluorescent probes. It can be used to study protein interactions and conformational changes.