RESEARCH: ALZHEIMERS
FOLDING PROJECT #18254 PROFILE

Alzheimer's disease is marked by clumps of a protein called tau. The project aims to figure out the best computer models to simulate how tau behaves, as these models can help us understand and treat Alzheimer's.

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.

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Alzheimer's disease

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

Alzheimer's disease is a brain disorder that slowly destroys memory and thinking skills. It affects millions of people worldwide and there is currently no cure.

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neurofibrillary tangles

Abnormal accumulations of tau protein inside neurons.

Neurofibrillary tangles are a hallmark of Alzheimer's disease. They are clumps of a protein called tau that build up in the brain and disrupt its function.

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tau protein

A microtubule-associated protein involved in stabilizing neuronal structure.

Tau is a protein that helps keep nerve cells healthy and functioning properly. In Alzheimer's disease, tau becomes twisted and tangled, disrupting the cell's ability to work.

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microtubules

Tubular structures within cells that provide structural support and facilitate transport.

Microtubules are long, hollow tubes found inside cells. They help maintain the cell's shape, move organelles around, and are involved in processes like cell division.

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Intrinsically Disordered Protein (IDP)

Proteins that lack a stable three-dimensional structure under physiological conditions.

Intrinsically Disordered Proteins are proteins that don't have a fixed shape. They can change shape easily depending on their environment and interactions with other molecules.

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FRET

Förster Resonance Energy Transfer.

FRET is a technique used to study the interactions between molecules by measuring the transfer of energy between them.

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force fields

Parameters that govern the interactions between atoms in a molecular simulation.

Force fields are mathematical descriptions of how atoms interact with each other. They are used in computer simulations to model the behavior of molecules.