RESEARCH: ALZHEIMERS
FOLDING PROJECT #18258 PROFILE

Alzheimer's disease is caused by a protein called tau clumping up in the brain. Scientists are using computer simulations to study how tau behaves and find the best way to model it. This could lead to new treatments for Alzheimer's and other brain diseases.

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 serious brain condition that causes memory problems, thinking difficulties, and changes in personality. It's the most common cause of dementia, affecting millions of people worldwide. There is no cure for Alzheimer's, but treatments can help manage symptoms.

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Neurofibrillary tangles

Abnormal accumulations of tau protein found within nerve cells in the brain.

Neurofibrillary tangles are clumps of a protein called tau that form inside brain cells. They're a hallmark feature of Alzheimer's disease and other neurodegenerative disorders. These tangles disrupt normal cell function and contribute to brain damage.

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Tau protein

A microtubule-associated protein involved in stabilizing neuronal structure.

Tau protein is a key component of brain cells that helps maintain their shape and stability. In Alzheimer's disease, tau becomes abnormal and clumps together, forming neurofibrillary tangles which damage the brain.

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Microtubules

Hollow tubes made of protein that provide structural support and transport within cells.

Microtubules are like tiny highways inside cells, helping to transport materials and maintain their shape. They're essential for many cellular processes, including cell division and nerve signal transmission.

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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. They can change shape depending on their environment and the other molecules they interact with. This flexibility allows them to perform many important functions in cells.

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Force field

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

Force fields are like the rules of physics for computer simulations of molecules. They determine how atoms attract and repel each other, influencing the shape and behavior of molecules in a simulation.

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FRET

Förster resonance energy transfer.

FRET is a technique used to study the interactions between molecules. It involves measuring the transfer of energy between two fluorescent molecules when they are close together.