RESEARCH: ALZHEIMERS
FOLDING PROJECT #18257 PROFILE

Alzheimer's disease is linked to abnormal tau protein clumps in the brain. Scientists are using computer simulations to study how tau behaves, aiming to find better treatments for Alzheimer's and other neurodegenerative diseases. They are testing different simulation methods to accurately represent tau's flexibility and interactions with water.

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 disorder characterized by memory loss and cognitive decline.

Alzheimer's disease is a brain disorder that slowly destroys memory and thinking skills. It is the most common cause of dementia, a general term for memory loss and other intellectual abilities severe enough to interfere with daily life. There is no cure for Alzheimer's, but treatments can help manage symptoms.

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neurofibrillary tangles

Abnormal accumulations of tau protein within neurons.

Neurofibrillary tangles are clumps of a protein called tau that form inside brain cells. These tangles disrupt the normal function of neurons and contribute to the progression of Alzheimer's disease.

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tau protein

A microtubule-associated protein involved in neuronal structure and function.

Tau protein is a vital part of brain cells. It helps stabilize structures called microtubules, which are essential for transporting nutrients and other materials within the cell. In Alzheimer's disease, tau protein malfunctions and forms tangles that damage neurons.

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microtubules

Hollow protein filaments that provide structural support and transport within cells.

Microtubules are long, thin tubes made of protein that act like the cell's internal scaffolding. They help maintain cell shape, move materials around inside the cell, and separate chromosomes during cell division.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a stable three-dimensional structure.

Intrinsically disordered proteins (IDPs) are unique because they don't have a fixed shape. Instead, their structures are flexible and can change depending on their environment. This makes them challenging to study using traditional methods.

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single molecule FRET

A technique used to measure the distance between two points in a molecule.

Single-molecule FRET is a powerful tool used to study the structure and dynamics of biomolecules. It involves using fluorescent molecules (called fluorophores) attached to different parts of a molecule. By measuring the energy transfer between these fluorophores, researchers can determine the distance between them.

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force field

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

Force fields are essential for molecular dynamics simulations. They define how atoms attract and repel each other, allowing researchers to simulate the movement and behavior of molecules over time.