RESEARCH: ALZHEIMERS
FOLDING PROJECT #18252 PROFILE

Alzheimer's disease is caused by tangled proteins called tau. Studying these tangles is hard because they don't have a fixed shape. This project will test different computer models to see which one best simulates how tau behaves, helping us understand Alzheimer's 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 these simulations.

p18251 - amber99sb-disp with tip4pd 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 affects memory, thinking, and behavior. It's the most common cause of dementia, a general term for memory loss and other intellectual abilities severe enough to interfere with daily life. There are no cures for Alzheimer's, but treatments can help manage symptoms.

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Neurofibrillary tangles

Abnormal accumulations of tau protein inside neurons.

Neurofibrillary tangles are clumps of a protein called tau found inside brain cells. They are a hallmark of Alzheimer's disease and other neurodegenerative conditions. These tangles disrupt the normal function of brain cells, leading to their death and contributing to the cognitive decline seen in these diseases.

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Tau protein

A microtubule-associated protein involved in stabilizing microtubules.

Tau is a protein that plays an essential role in maintaining the structure and function of brain cells. It binds to microtubules, which are long, thin tubes that provide support and transport within cells. In Alzheimer's disease, tau becomes abnormally twisted and forms tangles, disrupting neuronal function.

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Microtubules

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

Microtubules are essential components of the cytoskeleton, a network of proteins that provides shape and support to cells. They act as tracks for transporting molecules and organelles within the cell and play a crucial role in cell division and other cellular processes.

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Intrinsically Disordered Protein (IDP)

Proteins that lack a defined three-dimensional structure.

Intrinsically disordered proteins (IDPs) are a class of proteins that do not have a stable, fixed shape. They exist in a flexible, dynamic state and can adopt different conformations depending on their environment or interactions with other molecules. IDPs often play important roles in cellular signaling, regulation, and protein-protein interactions.

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Force field

A set of parameters used in molecular simulations to describe the interactions between atoms.

Force fields are mathematical models that describe the forces acting between atoms in a molecule. They are essential for molecular simulations, which allow scientists to study the behavior of molecules at an atomic level. Force fields are often parameterized based on experimental data and used to simulate various processes, such as protein folding, drug binding, and chemical reactions.

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Water models

Mathematical representations of water molecules used in molecular simulations.

Water models are simplified representations of water molecules used in computer simulations. They capture the essential properties of water, such as its polarity and hydrogen bonding capabilities. Accurate water models are crucial for simulating biological systems, as water plays a vital role in many cellular processes.