RESEARCH: ALZHEIMERS
FOLDING PROJECT #18263 PROFILE

Alzheimer's disease is bad for your memory and there's no cure. This project studies tau protein, which gets tangled up in Alzheimer's brains. Scientists are using computer models to see how different settings in the model affect how well it mimics real tau protein. They hope this will help everyone studying these tricky proteins.

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 182[51-56,58,61,62].

and 12000 MiB to run 182[57,60] 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 p18260- amber99sb-star-ILDN with tip4p water p18261- amber19sb with opc3 pol water p18262 - charmm36m with tip3p water p18263 - amber99sb-star-ILDN 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 causes memory problems, thinking difficulties, and changes in behavior. It affects millions of people worldwide and currently has no cure. Researchers are working hard to understand the disease and develop effective treatments.

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Neurofibrillary tangles

Abnormal accumulations of tau protein inside nerve cells.

Neurofibrillary tangles are a hallmark of Alzheimer's disease. They are clumps of twisted fibers made up of a protein called tau that build up inside brain cells. These tangles disrupt normal cell function and contribute to the progression of the disease.

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Tau protein

A protein that helps stabilize microtubules in nerve cells.

Tau is a protein crucial for the healthy function of brain cells. It plays a vital role in maintaining the structure and stability of microtubules, which are essential for transporting nutrients and other materials within neurons. In Alzheimer's disease, tau becomes abnormal and forms tangles, disrupting normal cell function.

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Microtubules

Hollow tubes made of protein that help maintain cell shape and transport materials.

Microtubules are essential components of the cytoskeleton, a network of protein fibers that provides structure and support to cells. They play a crucial role in various cellular processes, including cell division, movement, and the transport of organelles and other molecules.

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Cytoskeleton

A network of protein fibers that provides support and shape to cells.

The cytoskeleton is a dynamic network of protein filaments that extends throughout the cytoplasm of cells. It plays a vital role in maintaining cell shape, facilitating movement, transporting materials within cells, and organizing cellular structures.

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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. Unlike most proteins, which fold into specific structures, IDPs exist in a flexible and dynamic state. This allows them to interact with other molecules in various ways and perform diverse functions.

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Single molecule FRET experiments

A method used to study the distance between two molecules in real time.

Single molecule FRET experiments involve attaching fluorescent tags to specific molecules and measuring the energy transfer between them. By analyzing the changes in fluorescence, researchers can determine the distance between the tagged molecules and gain insights into their interactions and dynamics.

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Force field

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

Force fields are essential components of molecular dynamics simulations. They provide the rules governing how atoms interact with each other, allowing researchers to simulate the behavior of molecules over time.

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Water models

Representations of water molecules used in simulations.

Water models are crucial for accurately simulating biological systems. They capture the dynamic behavior of water molecules and their interactions with other atoms.

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Atomistic detail

A level of detail that represents individual atoms in a simulation.

Atomistic detail refers to the ability of a simulation to capture the movements and interactions of individual atoms. It allows researchers to study complex molecular systems at a very precise level.