RESEARCH: ALZHEIMERS
FOLDING PROJECT #18262 PROFILE

Alzheimer's disease is linked to abnormal tau protein buildup in the brain. Studying tau is hard because it's flexible and doesn't have a fixed shape. This project tests different computer simulation methods to see which best mimics how tau behaves, hoping to shed light on Alzheimer's and help researchers study other similar 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].

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 tip4pd water p18261- amber19sb with opc3 pol water p18262 - 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. It gets worse over time and can lead to difficulties with daily activities. There is currently no cure for Alzheimer's, but treatments can help manage symptoms.

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Neurofibrillary tangles

Abnormal accumulations of tau protein inside nerve cells.

Neurofibrillary tangles are twisted fibers of a protein called tau found in the brains of people with Alzheimer's. They interfere with the function of brain cells and contribute to the disease's progression.

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Tau protein

A microtubule-associated protein involved in stabilizing and regulating neuronal structure.

Tau is a protein that helps maintain the shape and stability of nerve cells. In Alzheimer's disease, tau becomes abnormal and forms tangles, which damage brain cells.

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Microtubules

Long, hollow protein fibers that provide structural support and transport within cells.

Microtubules are essential components of the cell's internal framework. They help maintain cell shape, facilitate movement of materials within cells, and play a role in cell division.

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Intrinsically Disordered Protein (IDP)

A protein that lacks a defined three-dimensional structure in solution.

Intrinsically disordered proteins are flexible and can adopt different shapes depending on their environment. This makes them challenging to study using traditional methods.

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Single molecule FRET

A technique used to study protein interactions and conformational changes at the single-molecule level.

Single molecule FRET measures the fluorescence resonance energy transfer between two fluorescent molecules attached to a protein. This allows researchers to track the movement and interactions of individual protein molecules.

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Force fields

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

Force fields are used in molecular dynamics simulations to calculate the forces acting on atoms. Accurate force fields are essential for simulating biological systems.

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Water models

Mathematical models that describe the interactions between water molecules.

Water models are used in molecular dynamics simulations to account for the role of water in biological systems. Accurate water models are crucial for simulating protein folding and other biomolecular processes.