RESEARCH: ALZHEIMERS
FOLDING PROJECT #18251 PROFILE

Alzheimer's disease damages brain cells and causes memory loss. A key protein called tau misbehaves in this disease, making it hard to study. Scientists are using computer simulations with different settings to better understand how tau works and find ways to 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. 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 causes problems with memory, thinking, and behavior. It slowly gets worse over time and eventually leads to death.

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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 feature of Alzheimer's disease and other neurodegenerative disorders.

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tau protein

A protein that helps stabilize microtubules in neurons.

Tau is a protein that plays an important role in the structure and function of nerve cells. In Alzheimer's disease, tau becomes abnormal and forms tangles.

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microtubules

Protein filaments that provide structural support and facilitate transport within cells.

Microtubules are tiny tubes made of protein that help give cells their shape and act as tracks for transporting materials inside the cell.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a stable three-dimensional structure.

Intrinsically disordered proteins (IDPs) are proteins that don't have a fixed shape. Their flexibility allows them to perform many different functions in the cell.

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single molecule FRET experiments

A technique used to study the structure and dynamics of biomolecules at the single-molecule level.

Single molecule FRET experiments use fluorescent tags to track the movements of individual molecules. This allows researchers to study how proteins fold and interact with other molecules.

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force fields

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

Force fields are mathematical models that describe how atoms interact with each other. They are used in computer simulations to predict the behavior of molecules.

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water models

Representations of water molecules used in molecular simulations.

Water models are mathematical representations of water molecules. They are used in computer simulations to account for the effects of water on biomolecules.