RESEARCH: ALZHEIMERS
FOLDING PROJECT #18255 PROFILE

Alzheimer's disease is linked to tangles of a protein called tau. The project relates to finding the best computer models to understand how tau behaves because it's hard to study directly. These models could help us learn about Alzheimer's and other 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 that causes memory loss, cognitive decline, and behavioral changes.

Alzheimer's disease is a serious brain condition that affects thinking, memory, and behavior. People with Alzheimer's may struggle with everyday tasks and eventually lose the ability to care for themselves. There is no cure 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 that form inside brain cells. These tangles are a hallmark of Alzheimer's disease and other neurodegenerative disorders.

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Tau protein

A microtubule-associated protein that plays a role in stabilizing neuronal structures.

Tau is a protein found in brain cells. It helps to support the structure of neurons and keep them healthy. In Alzheimer's disease, tau becomes tangled and clumps together, damaging the brain.

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Microtubules

Tubular protein structures that provide structural support and facilitate intracellular transport.

Microtubules are long, hollow tubes made of protein that help cells maintain their shape and move materials around. They play a crucial role in cell division and other important cellular processes.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a stable, defined three-dimensional structure.

Intrinsically disordered proteins are unique because they don't have a fixed shape. They can adopt different conformations depending on their environment and interactions with other molecules. This flexibility allows them to perform diverse functions in the cell.

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Single molecule FRET

A technique used to measure the distance between two molecules labeled with fluorescent probes.

Single molecule FRET (Förster Resonance Energy Transfer) is a powerful tool for studying the structure and dynamics of biomolecules. It allows researchers to track the movement of individual molecules and measure their interactions in real time.

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Force fields

Mathematical models that describe the interactions between atoms in a molecule.

Force fields are used in computer simulations to predict how molecules will behave. They provide a way to simulate the forces that act between atoms, allowing researchers to study chemical reactions, protein folding, and other complex phenomena.

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Water models

Mathematical representations of water molecules used in computer simulations.

Water models are essential for simulating biological systems because water plays a critical role in many cellular processes. Accurate water models allow researchers to capture the effects of hydration on protein structure, folding, and function.