RESEARCH: ALZHEIMERS
FOLDING PROJECT #18260 PROFILE

Alzheimer's disease is marked by tangles of a protein called tau. Tau normally helps cells stay organized, but when it misbehaves, it can cause problems. The project relates to figuring out the best computer models to study how tau behaves. These models could help us understand Alzheimer's and develop new treatments.

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 these simulations.

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 p18259 - amber19sb with opc3 pol water p18260- amber99sb-star-ILDN with tip4pd water p18261- charmm36m with tip3p water.

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Alzheimer's disease

A progressive neurodegenerative disease characterized by memory loss and cognitive decline.

Alzheimer's disease is a serious brain disorder that gradually destroys memory and thinking skills. It affects millions of people worldwide and is the most common cause of dementia. There is currently no cure for Alzheimer's, but treatments can help manage symptoms.

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neurofibrillary tangles

Abnormal accumulations of tau protein inside nerve cells.

Neurofibrillary tangles are twisted fibers that form inside brain cells in people with Alzheimer's disease. They are one of the hallmarks of the disease and contribute to the death of neurons.

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tau protein

A microtubule-associated protein that plays a role in stabilizing microtubules.

Tau is a protein found in brain cells that helps maintain the structure of microtubules. Microtubules are essential for many cellular functions, including transport and cell division. In Alzheimer's disease, tau becomes abnormally tangled and contributes to neuronal damage.

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microtubules

Hollow tubes made of protein that form part of the cytoskeleton.

Microtubules are long, thin structures found inside cells that play a vital role in cell shape, movement, and transport. They are essential for many cellular processes, such as cell division and intracellular transport.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a fixed three-dimensional structure.

Intrinsically disordered proteins (IDPs) are a unique class of proteins that do not have a stable, defined shape. They exist in a flexible, constantly changing state, allowing them to perform diverse functions.

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force field

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

Force fields are used in computer simulations to model the behavior of molecules. They define how atoms interact with each other, such as through electrostatic forces or van der Waals forces.

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FRET

Förster Resonance Energy Transfer.

FRET is a technique used to measure the distance between two molecules labeled with fluorescent tags. It has applications in studying protein interactions and molecular dynamics.